Info

1 gene found

refine your query bookmark your results download as json / API call

		NCBI ENSEMBL UCSC GeneCards ClinVar PubMed
		Position: 17:42313324-42388442 (GRCh 38) NCBI synonyms: APRF, FLJ20882, MGC16063, HIES, ADMIO, ADMIO1 Paralogs: STAT1 (51%) STAT2 (38%) STAT4 (46%) STAT5A (30%) STAT5B (30%) STAT6 (23%) Gene Summaries OMIM: ► ▼ SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3 102582 CLONING Akira et al. (1994) purified acute-phase response factor (APRF), also designated STAT3, and cloned the cDNA. At the amino acid level, APRF exhibited 52.5% overall homology with p91, a component of the interferon (IFN)-stimulated gene factor-3 complexes. Also see STAT1 (600555). Caldenhoven et al. (1996) reported the cloning of a cDNA encoding a variant of the transcription factor STAT3, designated STAT3-beta, that was isolated by screening an eosinophil cDNA library. Compared to wildtype STAT3, STAT3-beta lacks an internal domain of 50 bp located near the C terminus. This splice product is a naturally occurring isoform of STAT3 and encodes an 80-kD protein. Using Northern blot analysis, Miyoshi et al. (2001) detected expression of a 5.0-kb mouse Stat3 transcript that was highest in liver and heart, intermediate in lung, spleen, brain, testis, and kidney, and lowest in muscle. GENE FUNCTION Acute-phase response factor is a latent cytoplasmic transcription factor that is rapidly activated in response to interleukin-5 (IL5; 147850), interleukin-6 (IL6; 147620), epidermal growth factor (131530), leukemia inhibitory factor (159540), oncostatin M (165095), interleukin-11 (147681), and ciliary neurotrophic factor (118945). After activation, the 89-kD protein binds to IL6 response elements identified in the promoter regions of various IL6-induced plasma-protein and intermediate-early genes. Lutticken et al. (1994) demonstrated that the above listed cytokines cause tyrosine phosphorylation of the APRF. Protein kinases of the JAK family (e.g., 147795) were also rapidly tyrosine phosphorylated, and both APRF and JAK1 associated with the signal transducer gp130 (IL6ST; 600694). Akira et al. (1994) suggested that APRF may play a major role in the gp130-mediated signaling pathway. Binding of IL5 to its specific receptor activates JAK2 (147796) which leads to the tyrosine phosphorylation of STAT3 proteins. Caldenhoven et al. (1996) found that STAT3-beta, like STAT3, is phosphorylated on tyrosine and binds to the pIRE from the ICAM1 (147840) promoter after IL5 stimulation. Coexpression of STAT3-beta inhibits the transactivation potential of STAT3. These results suggested that STAT3-beta functions as a negative regulator of transcription. The leptin receptor (601007) is found in many tissues in several alternatively spliced forms, raising the possibility that leptin (164160) exerts effects on many tissues including the hypothalamus. The leptin receptor is a member of the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. In order to identify the sites of leptin action in vivo, Vaisse et al. (1996) assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor, where they are subsequently phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus, where they bind DNA and activate transcription. The investigators assayed the activation of STAT proteins in response to leptin in a variety of mouse tissues known to express the leptin receptor, Obr. Leptin injection activated Stat3 but no other STAT protein in the hypothalamus of ob/ob and wildtype mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. The dose-dependent activation of STAT3 by leptin was first observed after 15 minutes and later at 30 minutes. The data indicated to Vaisse et al. (1996) that the hypothalamus is a direct target of leptin action and this activation is critically dependent on the gp130-like leptin receptor isoform missing in db/db mice. Pfeffer et al. (1997) found that STAT3, a transcription factor for acute phase response genes, acts as an adaptor molecule in signal transduction from the type I interferon receptor. They found that it binds to a conserved sequence in the cytoplasmic tail of the IFNAR1 (107450) chain of the receptor and undergoes interferon-dependent tyrosine phosphorylation. The p85 regulatory subunit of phosphatidylinositol 3-kinase, which activates a series of serine kinases, was found to bind to phosphorylated STAT3 and subsequently to undergo tyrosine phosphorylation. The authors concluded that STAT3 acts as an adaptor to couple another signaling pathway to the interferon receptor. The cytokines LIF (159540) and BMP2 (112261) signal through different receptors and transcription factors, namely STATs and SMADs, respectively. Nakashima et al. (1999) found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 (602700) interacted physically with STAT3 at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 (601595) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors. Foley et al. (2002) demonstrated that synthesis of STAT3-beta by erythroleukemia and primary erythroid progenitor cells treated with IL6 silences gamma-globin expression. They identified the STAT3-like binding sequence in both the A-gamma (142200) and G-gamma (142250) promoters. Ram et al. (2000) studied the roles of the MAP kinases (see MAPK1, 176948) and STAT3 in transformation of NIH 3T3 cells by Q205L Go-alpha (see 139311). Expression of Q205L Go-alpha in NIH 3T3 cells activated STAT3. Coexpression of dominant-negative STAT3 inhibited Q205L Go-alpha-induced transformation of NIH 3T3 cells and activation of endogenous STAT3. Ram et al. (2000) concluded that STAT3 can function as a downstream effector for Q205L Go-alpha and mediate its biologic effects. In many human cancers and transformed cell lines, STAT3 is persistently activated, and in cell culture, active STAT3 is either required for transformation, enhances transformation, or blocks apoptosis. Bromberg et al. (1999) reported that substitution of 2 cysteine residues within the C-terminal loop of the SH2 domain of the murine Stat3 gene produced a molecule that dimerized spontaneously, bound to DNA, and activated transcription. In immortalized fibroblasts, this mutant Stat3 molecule caused cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the authors concluded that the activated STAT3 molecule by itself can mediate cellular transformation, and the experiments focused attention on the importance of constitutive STAT3 activation in human tumors. STAT proteins become phosphorylated on tyrosine and translocate to the nucleus after stimulation of cells with growth factors or cytokines. Simon et al. (2000) showed that the RAC1 guanosine triphosphatase (602048) can bind to and regulate STAT3 activity. Dominant-negative RAC1 inhibited STAT3 activation by growth factors, whereas activated RAC1 stimulated STAT3 phosphorylation on both tyrosine and serine residues. Moreover, activated RAC1 formed a complex with STAT3 in mammalian cells. Yeast 2-hybrid analysis indicated that STAT3 binds directly to active but not inactive RAC1 and that the interaction occurs via the effector domain. Simon et al. (2000) concluded that RAC1 may serve as an alternative mechanism for targeting STAT3 to tyrosine kinase signaling complexes. Chung et al. (1997) identified PIAS3 (605987) as an inhibitor of STAT3 signaling. Using transient transfection methods, Scoles et al. (2002) showed that both schwannomin (NF2; 607379) and human growth factor-regulated tyrosine kinase substrate HRS (HGS; 604375) inhibited STAT3 activation, and that schwannomin suppressed STAT3 activation mediated by IGF1 (147440) treatment in a human schwannoma cell line. Schwannomin inhibited STAT3 and STAT5 (601511) phosphorylation in a rat schwannoma cell line. Schwannomin with the pathogenic missense mutation Q538P (607379.0006) failed to bind HRS and did not inhibit STAT5 phosphorylation. The authors hypothesized that schwannomin requires HRS interaction to be fully functionally active and to inhibit STAT activation. Tyr1138 of the leptin receptor long form (LRb; see 601007) mediates activation of the transcription factor STAT3 during leptin (164160) action. To investigate the contribution of STAT3 signaling to leptin action in vivo, Bates et al. (2003) replaced the gene encoding the leptin receptor (Lepr) in mice with an allele coding for replacement of tyr1138 in LRb with a serine residue that specifically disrupts the LRb-STAT3 signal. Like db/db mice, Lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short, and diabetic, s/s mice are fertile, long, and less hyperglycemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY; 162640) is elevated in db/db mice but not in s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. Bates et al. (2003) concluded that LRb-STAT3 signaling mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth, and glucose homeostasis. Using wildtype STAT3 and an activation mutant, STAT3(Y705F), Bhattacharya and Schindler (2003) demonstrated the existence of a basal nuclear export pathway independent of tyrosine phosphorylation and, by extension, implied the existence of a basal nuclear import pathway. They identified 3 nuclear export signal (NES) elements, 1 involved in poststimulation export and 2 that regulate basal nuclear export, and concluded that STAT3 nuclear export is dependent on multiple NES elements. Zhang et al. (2003) stated that phosphorylation of ser727 is required for STAT3 activation by diverse stimuli, including ultraviolet (UV) irradiation. They presented evidence that phosphorylation of ser727 involves a signaling pathway that includes ATM (607585), MAPKs, and RSK2 (300075), as well as other downstream kinases or cofactors. In addition, RSK2-mediated ser727 phosphorylation was required for basal and UV-stimulated STAT3 transcriptional activities. Lovato et al. (2003) found that STAT3 and STAT4 (600558) were constitutively activated in intestinal T cells from Crohn disease patients (see IBD22, 612380), but not in healthy volunteers. Other STAT proteins were not constitutively activated. The STAT3-regulated protein SOCS3 (604176) was also constitutively expressed in Crohn disease T cells. Lovato et al. (2003) concluded that there is abnormal STAT/SOCS signaling in Crohn disease. Yuan et al. (2005) showed that in response to cytokine treatment, STAT3 is acetylated on a single lysine residue, lys685. Histone acetyltransferase p300 (602700)-mediated STAT3 acetylation on lys685 was reversible by type I histone deacetylase (see 605314). Using a prostate cancer cell line that lacks STAT3, they established cell lines expressing wildtype STAT3 or a STAT3 mutant containing a lys685-to-arg substitution. Their findings showed that lys685 acetylation was critical for STAT3 to form stable dimers required for cytokine-stimulated DNA binding and transcriptional regulation, to enhance transcription of cell growth-related genes, and to promote cell cycle progression in response to treatment with oncostatin M (165095). McLoughlin et al. (2005) showed that Il6 -/- mice with Staphylococcus epidermidis-induced peritoneal inflammation exhibited impaired T-cell recruitment with reduced expression of chemokine receptors (e.g., CCR5; 601373) and defective expression of chemokines (e.g., CCL4; 182284). Experiments with knockin mice expressing mutated forms of gp130 (IL6ST; 600694) indicated that Il6-mediated T-cell recruitment required gp130-dependent Stat3 activation. Kokoeva et al. (2005) demonstrated that centrally administered ciliary neurotrophic factor (CNTF; 118945) induces cell proliferation and feeding centers of the murine hypothalamus. Many of the newborn cells expressed neuronal markers and showed functional phenotypes relevant for energy balance control, including the capacity for leptin-induced phosphorylation of STAT3. Coadministration of the mitotic blocker Ara-C eliminated the proliferation of neural cells and abrogated the long-term, but not the short-term, effect of CNTF on body weight. Kokoeva et al. (2005) concluded that their findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis. T-cell lymphomas lose expression of SHP1 (PTPN6; 176883) due to DNA methylation of its promoter. Zhang et al. (2005) demonstrated that malignant T cells expressed DNMT1 (126375) and that STAT3 could bind sites in the SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 (601241) formed complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1 and STAT3 siRNA induced DNA demethylation in malignant T cells and expression of SHP1. Zhang et al. (2005) concluded that STAT3 may transform cells by inducing epigenetic silencing of SHP1 in cooperation with DNMT1 and HDAC1. Most Toxoplasma gondii isolates in Europe and North America belong to 3 clonal lines, designated types I, II, and III. Using microarray, immunofluorescence, and Western blot analyses, Saeij et al. (2007) found that STAT3 and STAT6 (601512) were activated predominantly in fibroblasts infected with types I and III, rather than type II, T. gondii. They determined that the T. gondii Rop16 protein kinase mediated the strain-specific activation of STAT3 and STAT6. Saeij et al. (2007) noted that their results correlated with previous findings showing that type II T. gondii induces high levels of IL12A (161560) and IL12B (161561) secretion, whereas type I T. gondii induces STAT3 activation and prevents IL12 expression. Ying et al. (2008) demonstrated that, contrary to long-held belief, extrinsic stimuli are dispensable for the derivation, propagation, and pluripotency of embryonic stem (ES) cells. Self-renewal is enabled by the elimination of differentiation-inducing signaling from mitogen-activated protein kinase (see 176948). Additional inhibition of glycogen synthase kinase-3 (see 606784) consolidates biosynthetic capacity and suppresses residual differentiation. Complete bypass of cytokine signaling was confirmed by isolating ES cells genetically devoid of STAT3. Ying et al. (2008) concluded that ES cells have an innate program for self-replication that does not require extrinsic instruction. The authors suggested that this property may account for their latent tumorigenicity. Bong et al. (2007) found that vertebrate ephrin B1 (EFNB1; 300035) interacted with Stat3 in a tyrosine phosphorylation-dependent manner, resulting in phosphorylation and enhanced transcriptional activation of Stat3. Wegrzyn et al. (2009) provided evidence that Stat3 is present in the mitochondria of mouse cultured cells and primary tissues, including the liver and heart. In Stat3-null cells, the activities of complexes I and II of the electron transport chain were significantly decreased. Wegrzyn et al. (2009) identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the electron transport chain. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the electron transport chain. Wegrzyn et al. (2009) concluded that Stat3 is required for optimal function of the electron transport chain, which may allow it to orchestrate responses to cellular homeostasis. Gough et al. (2009) reported that malignant transformation by activated Ras (190020.0001) is impaired without STAT3, in spite of the inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation. Moreover, STAT3 mutants that cannot be tyrosine-phosphorylated, that are retained in the cytoplasm, or that cannot bind DNA nonetheless supported Ras-mediated transformation. Unexpectedly, STAT3 was detected within mitochondria, and exclusive targeting of STAT3 to mitochondria without nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3 sustained altered glycolytic and oxidative phosphorylation activities characteristic of cancer cells. Thus, Gough et al. (2009) concluded that, in addition to its nuclear transcriptional role, STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation. Chaudhry et al. (2009) demonstrated that pathogenic IL17 (603149)-producing T-helper cell (Th17) responses in mice are restrained by CD4+ regulatory cells, or T(regs). This suppression was lost upon T(reg)-specific ablation of Stat3, a transcription factor critical for Th17 differentiation, and resulted in the development of a fatal intestinal inflammation. Chaudhry et al. (2009) concluded that T(regs) adapt to their environment by engaging distinct effector response-specific suppression modalities upon activation of STAT proteins that direct the corresponding class of the immune response. Carro et al. (2010) used reverse engineering and an unbiased interrogation of a glioma-specific regulatory network to reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors, C/EBP-beta (189965) and STAT3, emerged as synergistic initiators and master regulators of mesenchymal transformation. Ectopic coexpression of C/EBP-beta and STAT3 reprogrammed neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the 2 factors in glioma cells led to collapse of the mesenchymal signature and reduced tumor aggressiveness. In human glioma, expression of C/EBP-beta and STAT3 correlated with mesenchymal differentiation and predicted poor clinical outcome. Carro et al. (2010) concluded that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells. GENE STRUCTURE Miyoshi et al. (2001) determined that the mouse Stat3 gene contains 24 exons and spans 30 kb. The translation initiation codon is in exon 2, and the stop codon is in exon 24. The gene has a single promoter. MAPPING Choi et al. (1996) used fluorescence in situ hybridization to map the STAT3 gene to chromosome 17q21. Miyoshi et al. (2001) determined that the mouse Stat3 and Stat5a (601511) genes are located next to each other in a tail-to-tail orientation on chromosome 11, with their polyadenylation sites 3.0 kb apart. The order and orientation of genes at this locus, Ptrf (603198)--Stat3--Stat5a--Stat5b (604260)--Lgp1 (608587)--Hcrt (602358), are identical in the region of syntenic homology on human chromosome 17q21. MOLECULAR GENETICS - Hyper-IgE Syndrome Minegishi et al. (2007) showed that dominant-negative mutations in the STAT3 gene result in the classic multisystem hyper-IgE syndrome (HIES; 147060), a disorder of both immunity and connective tissue. They found that 8 of 15 unrelated nonfamilial HIES patients had heterozygous STAT3 mutations (see, e.g., 102582.0001-102582.0003). None of the parents or sibs of the patients had the mutant allele, suggesting that the 5 different mutations, all of which were located in the STAT3 DNA-binding domain, occurred de novo. All 5 mutants were nonfunctional by themselves and showed dominant-negative effects when coexpressed with wildtype STAT3. Holland et al. (2007) likewise found mutations in STAT3 in the hyper-IgE syndrome. They found increased levels of proinflammatory gene transcripts in unstimulated peripheral blood neutrophils and mononuclear cells from patients with HIES as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide had higher tumor necrosis factor-alpha (TNFA; 191160) levels than did identically treated cells from unaffected individuals. In contrast, the cells from patients with HIES generated lower levels of monocyte chemoattractant protein-1 (MCP1; 158105) in response to the presence of interleukin-6, suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. Holland et al. (2007) identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of HIES. Eighteen discrete mutations, 5 of which were hotspots, were predicted to affect directly the DNA-binding and SRC homology-2 (SH2) domains. - Associations Pending Confirmation For discussion of a possible association between variation in the STAT3 gene and Crohn disease, see IBD22 (612380). For discussion of a possible association between variation in the STAT3 gene and susceptibility to multiple sclerosis, see MS (126200). ANIMAL MODEL Alternative splicing of the STAT3 gene produces 2 isoforms, STAT3-alpha and a dominant-negative variant, STAT3-beta. In STAT3-beta, the 55 C-terminal residues of STAT3-alpha, spanning the intrinsic transactivation domain, are replaced by 7 distinct residues. Yoo et al. (2002) generated Stat3-beta-deficient mice by gene targeting. Despite intact expression and phosphorylation of Stat3-alpha, overall Stat3 activity was impaired in Stat3-beta -/- cells. Global comparison of transcription in Stat3-beta +/+ and Stat3-beta -/- cells revealed stable differences. Stat3-beta-deficient mice exhibited diminished recovery from endotoxic shock and hyperresponsiveness of a subset of endotoxin-inducible genes in liver. The hepatic response to endotoxin in wildtype mice was accompanied by a transient increase in the ratio of Stat3-beta to Stat3-alpha. These findings indicated a critical role for Stat3-beta in the control of systemic inflammation. Welte et al. (2003) generated a strain of mice with tissue-specific disruption of Stat3 in bone marrow cells during hematopoiesis. The deletion caused death of the mice within 4 to 6 weeks after birth with Crohn disease-like pathogenesis (see 266600) in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of myeloid lineage, both in vivo and in vitro. The authors presented evidence that STAT3 may have an essential regulatory function in the innate immune system. In particular, STAT3 may play a critical role in the control of mucosal immune tolerance. A dramatic expansion of myeloid lineages, causing massive infiltration of the intestine with neutrophils, macrophages, and eosinophils, was thought to be caused by pseudoactivated innate immune responses to bacterial lipopolysaccharide as a result of the STAT3 deletion during hematopoiesis. In cardiomyocyte-specific Stat3 knockout mice, Jacoby et al. (2003) observed significantly more apoptosis after lipopolysaccharide treatment than in wildtype mice, and Stat3 -/- cardiomyocytes secreted significantly more TNFA (191160) in response to lipopolysaccharide than wildtype. Mice with cardiomyocyte-specific Stat3 deficiency spontaneously developed heart dysfunction with age, and histologic examination of aged mice revealed a dramatic increase in cardiac fibrosis compared to wildtype. Jacoby et al. (2003) concluded that STAT3 is crucial in cardiomyocyte resistance to inflammation and other acute injury and in the pathogenesis of age-related heart failure. Wang et al. (2004) showed that constitutive activation of Stat3 suppressed tumor expression of proinflammatory mediators in mice. Introducing Stat3-beta, a dominant-negative variant, or Stat3 antisense into mouse tumor cell lines increased expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. Wang et al. (2004) concluded that STAT3 signaling in tumors negatively regulates inflammation, dendritic cell activity, and T-cell immunity. They proposed that selective inhibition of STAT3 signaling would have not only antitumor effects by suppressing growth and inducing apoptosis, but would also activate innate and adaptive antitumor immunity. Using gene targeting, Maritano et al. (2004) showed that in vivo Stat3-beta is not a dominant-negative factor. In the absence of Stat3-alpha, Stat3-beta rescued the embryonic lethality of the null mutation and could induce expression of specific Stat3 target genes. However, Stat3-alpha was essential for modulating cellular responses to Il6 and mediating Il10 (124092) function in macrophages. Inoue et al. (2004) showed that mice with liver-specific deficiency of STAT3, generated using the Cre-loxP system, showed insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC1A; 604517), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations, and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus (222100, 125853). Hokuto et al. (2004) showed that cell-selective deletion of Stat3 in mouse respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function. However, exposure of adult Stat3-deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress, as well as increased epithelial cell injury and inflammatory responses. Surfactant proteins and lipids were decreased or absent in alveolar lavage material. Intratracheal treatment with exogenous surfactant protein B (SFTPB; 178640) improved survival and lung histology in Stat3-deleted mice during hyperoxia. Hokuto et al. (2004) concluded that expression of STAT3 in respiratory epithelial cells is not required for lung formation, but plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury. To assess the effect of Stat3 deficiency on mouse skin tumor development, Chan et al. (2004) used the tumor initiator 7,12-dimethylbenz(alpha)anthracene (DMBA) and the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in the 2-stage chemical carcinogenesis model. Stat3-deficient mice showed significantly reduced epidermal proliferation following treatment with TPA because of a defect in progression of the cell cycle from G1 to S phase; treatment with DMBA resulted in a significant increase in the number of apoptotic keratinocyte stem cells. Stat3-deficient mice were completely resistant to skin tumor development when DMBA was used as the initiator and TPA as the promoter. Abrogation of Stat3 function using a decoy oligonucleotide inhibited the growth of initiated keratinocytes possessing an activated Hras gene (190020), both in vitro and in vivo. Injection of Stat3 decoy into skin tumors inhibited their growth. Chan et al. (2004) concluded that STAT3 is required for de novo epithelial carcinogenesis through maintaining the survival of DNA-damaged stem cells and through mediating and maintaining the proliferation necessary for clonal expansion of initiated cells during tumor promotion. Using immunohistochemical analysis, Sano et al. (2005) demonstrated activated STAT3 in epidermal keratinocytes from human psoriatic lesions (see 177900). Transgenic mice with keratinocytes expressing a constitutively active Stat3 developed skin lesions, either spontaneously or in response to wounding, that closely resembled human psoriatic plaques; in transgenic keratinocytes there was upregulation of several molecules linked to the pathogenesis of psoriasis. The development of psoriatic lesions in the transgenic mice required cooperation between Stat3 activation in keratinocytes and activated T cells, and abrogation of Stat3 function by a decoy oligonucleotide inhibited the onset and reversed established psoriatic lesions. Using a mouse model of spinal cord injury, Okada et al. (2006) showed that Stat3 is a key regulator of reactive astrocytosis in the repair of injured tissue during the subacute phase (initial 14 days after injury). Selective disruption of the Stat3 gene in mice subjected to spinal cord injury resulted in limited migration of reactive astrocytes, widespread infiltration of inflammatory cells, and neural disruption and demyelination compared to wildtype mice. NCBI: NG_007370.1 The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020] Open Targets: ► ▼ ENSG00000168610 Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:16285960, PubMed:15653507, PubMed:17344214, PubMed:18242580, PubMed:18782771, PubMed:22306293, PubMed:23084476, PubMed:32929201, PubMed:28262505). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:16285960, PubMed:15653507, PubMed:17344214, PubMed:18782771, PubMed:28262505, PubMed:32929201). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): acetylation promotes its transcription activity and cell differentiation while deacetylation and oxidation of lysine residues by LOXL3 inhibits differentiation (PubMed:28262505, PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity). Following JAK/STAT signaling activation and as part of a complex with NFATC3 and NFATC4, binds to the alpha-beta E4 promoter region of CRYAB and activates transcription in cardiomyocytes (By similarity). {ECO:0000250\|UniProtKB:P42227, ECO:0000269\|PubMed:10688651, ECO:0000269\|PubMed:12359225, ECO:0000269\|PubMed:12873986, ECO:0000269\|PubMed:15194700, ECO:0000269\|PubMed:15653507, ECO:0000269\|PubMed:16285960, ECO:0000269\|PubMed:17344214, ECO:0000269\|PubMed:18242580, ECO:0000269\|PubMed:18782771, ECO:0000269\|PubMed:22306293, ECO:0000269\|PubMed:23084476, ECO:0000269\|PubMed:28065600, ECO:0000269\|PubMed:28262505, ECO:0000269\|PubMed:32929201}.
		ClinVar: 90 pathogenic or likely pathogenic variants in ClinVar. Gene constraints: synonymous: 1.219 missense: 7.374 LOF: 1 (from gnomAD) Orphanet: ► ▼ Autosomal dominant hyper-IgE syndrome (Disease) ORPHA:2314 germline assessed neonatal infancy autosomal dominant A very rare primary immunodeficiency disorder characterized by the clinical triad of high serum IgE (>2000 IU/ml), recurring staphylococcal skin abscesses, and recurrent pneumonia with formation of pneumatoceles. STAT3-related early-onset multisystem autoimmune disease (Disease) ORPHA:438159 germline gain of function assessed infancy childhood autosomal dominant A rare, genetic, lymphoproliferative syndrome characterized by early onset recurrent infections, lymphadenopathy with hepatosplenomegaly and variable autoimmune disorders, including hemolytic anemia, thrombocytopenia, neutropenia, enteropathy, type I diabetes, scleroderma, arthritis, atopic dermatitis, and inflammatory lung disease. Patients commonly have failure to thrive. Variable immunologic findings include decreased regulatory T-cells, hypogammaglobulinemia, and reduction in memory B cells. Acute promyelocytic leukemia (Disease) ORPHA:520 fusion gene assessed childhood adolescent adult elderly An aggressive form of acute myeloid leukemia (AML), characterized by arrest of leukocyte differentiation at the promyelocyte stage, due to a specific chromosomal translocation t(15;17) in myeloid cells, and manifests with easy bruising, hemorrhagic diathesis and fatigue. Chronic lymphoproliferative disorder of natural killer cells (Disease) ORPHA:512017 germline assessed A rare large granular lymphocyte leukemia characterized by persistent (> 6 months) natural killer cell lymphocytosis in the absence of clinical diagnosis of leukemia/lymphoma, autoimmune disease, or chronic viral infections. The clinical course is variable, but generally indolent. Patients often remain asymptomatic, or may present with clinical manifestations including vasculitic skin lesions, neutropenic infections, musculoskeletal symptoms, peripheral neuropathy, or splenomegaly. T-cell large granular lymphocyte leukemia (Disease) ORPHA:86872 somatic assessed adult T-cell large granular lymphocyte leukemia (T-cell LGL leukemia) is a lymphoproliferative malignancy that arises from the mature T-cell (CD3+) lineage. Isolated permanent neonatal diabetes mellitus (Disease) ORPHA:99885 germline gain of function assessed neonatal infancy antenatal autosomal dominant autosomal recessive Permanent neonatal diabetes mellitus (PNDM) is a monogenic form of neonatal diabetes (NDM, see this term) characterized by persistent hyperglycemia within the first 12 months of life in general, requiring continuous insulin treatment. HPO: ► ▼ Abnormality of the upper urinary tract Intellectual disability, severe Motor delay Hypotonia Ataxia Intellectual disability Pancreatic hypoplasia Global developmental delay Coma Achalasia Chronic infection Bone marrow hypercellularity Joint hypermobility Craniosynostosis Muscle weakness Lymphoma Autosomal dominant inheritance Bone pain Scoliosis Vascular dilatation Celiac disease Hodgkin lymphoma Abnormality of the dentition Bilateral ptosis Cleft palate Persistence of primary teeth Cutaneous abscess Reduced pancreatic beta cells Recurrent lower respiratory tract infections Diffuse alveolar hemorrhage Recurrent upper respiratory tract infections Renal tubular dysfunction Recurrent fractures Osteomyelitis Hepatosplenomegaly Productive cough Recurrent infections Lymphadenopathy Downturned corners of mouth Chronic mucocutaneous candidiasis Recurrent Staphylococcus aureus infections Abdominal pain Frontal bossing Bilateral tonic-clonic seizure Addictive alcohol use Anorexia Desquamative interstitial pneumonitis Peripheral axonal neuropathy Generalized myoclonic seizure Hypofibrinogenemia Apraxia Infantile onset Abnormal intestine morphology Recurrent respiratory infections Atelectasis Gangrene Dystrophic fingernails Vertigo Type I diabetes mellitus Cellulitis Skin vesicle Papule Metrorrhagia Skin ulcer Erythema Neonatal onset Juvenile onset Disseminated intravascular coagulation Autoimmune thrombocytopenia Leukocytosis Dehydration Fever Neutropenia in presence of anti-neutropil antibodies Anemia Generalized abnormality of skin Delayed eruption of teeth Short stature Decreased circulating antibody level Glycosuria Hyperglycemia Joint hyperflexibility Cough Childhood onset Hematuria Neurodevelopmental delay Lower-limb joint contracture Polyarticular arthritis Neonatal insulin-dependent diabetes mellitus Hypothyroidism Delayed puberty Stomatitis Increased circulating IgE level Purpura Eczematoid dermatitis Bruising susceptibility Pruritus Skin rash Eczema Petechiae Osteopenia Coarse facial features Abnormal hair morphology Abnormality of the face Autoimmune antibody positivity Arthrogryposis multiplex congenita High palate Gingival overgrowth Exertional dyspnea Gingivitis Gingival bleeding Ecchymosis Failure to thrive Intrauterine growth retardation Recurrent fungal infections Fatigue Chronic otitis media Recurrent pneumonia Interstitial pneumonitis Ketonuria Hearing impairment Hypertelorism Oral cavity bleeding Autoimmunity Abnormal heart morphology Exocrine pancreatic insufficiency Deeply set eye Retinopathy Hypovolemia Wide nose Wide nasal bridge Epistaxis Recurrent sinopulmonary infections Prominent metopic ridge Weight loss Paronychia Moderate albuminuria Abnormal bleeding Autoimmune hemolytic anemia Prominent forehead Eosinophilia Leukopenia Thrombocytopenia Pancytopenia Neutropenia OMIM: ► ▼ AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 1; ADMIO1 615952 no details in our DB, please see OMIM ► ▼ HYPER-IgE RECURRENT INFECTION SYNDROME 1, AUTOSOMAL DOMINANT; HIES1 147060 INHERITANCE: Autosomal dominant HEAD AND NECK: [Face]; Coarse facies; Asymmetric face; Prominent forehead; Mild prognathism; [Eyes]; Hypertelorism; [Nose]; Broad nose; Thickening of the soft tissue of the nose; [Mouth]; High-arched palate; [Teeth]; Retained primary teeth; Reduced resorption of primary tooth roots RESPIRATORY: Recurrent sinopulmonary infections; [Lung]; Pneumatocele formation SKELETAL: Joint hyperextensibility; Decreased bone mineral density; Recurrent fractures; [Skull]; Craniosynostosis (rare); [Spine]; Scoliosis; Vertebral body abnormalities SKIN, NAILS, HAIR: [Skin]; Eczema, severe; Recurrent skin abscesses IMMUNOLOGY: Recurrent Staphylococcus aureus infections; Abscesses are 'cold,' lacking erythema, heat, and swelling; Recurrent fungal infections LABORATORY ABNORMALITIES: Increased serum IgE; Eosinophilia MISCELLANEOUS: Onset in infancy MOLECULAR BASIS: Caused by mutation in the signal transducer and activator of transcription-3 gene (STAT3, 102582.0001 A number sign (#) is used with this entry because autosomal dominant hyper-IgE recurrent infection syndrome is caused by mutation in the STAT3 gene (102582). See also autosomal recessive HIES (243700), which is caused by mutation in the DOCK8 gene (611432), and tyrosine kinase-2 deficiency (611521), which is caused by mutation in the TYK2 gene (176941) and has been reported in a single patient. DESCRIPTION Hyper-IgE recurrent infection syndrome is a primary immunodeficiency disorder characterized by chronic eczema, recurrent Staphylococcal infections, increased serum IgE, and eosinophilia. Patients have a distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures (Buckley et al., 1972; Grimbacher et al., 1999). CLINICAL FEATURES Davis et al. (1966) reported 2 unrelated girls with lifelong histories of indolent Staphylococcal abscesses. Both had eczema soon after birth and had persistent weeping lesions on the ears and face. The abscesses were characterized as 'cold' because of the lack of surrounding warmth, erythema, or tenderness. Both girls had red hair and were fair-skinned. The authors suggested a defect in local resistance to Staphylococcal infection. Further study of these girls by White et al. (1969) revealed normal leukocyte functions. However, Hill et al. (1974) and Hill and Quie (1974) found a defect in neutrophil granulocyte chemotaxis and very high serum IgE levels in 4 girls with the disorder; 2 of the girls had been reported by Davis et al. (1966). Renner et al. (2007) provided a follow-up of 1 of the patients reported by Davis et al. (1966). At 50 years of age, the woman had had lifelong eczema, multiple atraumatic fractures, hyperkeratotic fingernails due to candida infection, recurrent Staphylococcal abscesses, and pneumonia with lung abscesses and pneumatocele formation. Two of her 3 sons and 1 grandson were also affected. Buckley et al. (1972) described 2 male patients with features of Job syndrome as originally described by Davis et al. (1966). Each boy had extremely high serum IgE levels as well as immediate cutaneous hypersensitivity reactions to Staphylococcus aureus and Candida albicans. The authors also noted joint hyperextensibility and asymmetric facies. Van Scoy et al. (1975) described a 20-year-old woman and her daughter who had recurrent bacterial infections and chronic mucocutaneous candidiasis. Laboratory studies showed marked elevation of serum IgE, defective neutrophil chemotaxis, and impaired lymphocyte response to candida antigen. The mother's brother, father, and paternal grandfather showed mild increases in IgE and mildly depressed chemotactic activity of neutrophils. Osteoporosis and a propensity to bone fracture, referred to by Brestel et al. (1982) as 'osteogenesis imperfecta tarda,' was a recognized feature of hyper-IgE syndrome. Kirchner et al. (1985) also noted the association of hyper-IgE syndrome with osteoporosis and recurrent fractures. Hoger et al. (1985) described the association with craniosynostosis and discussed 3 reported cases. Robinson et al. (1982) described a kindred brought to attention because of a 6-year-old girl who showed features of both the hyper-IgE syndrome and chronic granulomatous disease. Inheritance was possibly autosomal dominant. Laboratory studies showed impaired T cell responses. Donabedian and Gallin (1982) presented evidence suggesting that mononuclear cells from patients with the hyper-IgE recurrent infection syndrome produced an inhibitor of leukocyte chemotaxis. Donabedian and Gallin (1983) provided a review of 13 patients with hyper-IgE syndrome examined at the National Institutes of Health. Nine of the 13 had coarse facies, with broad nasal bridge, prominent nose, and irregularly proportioned cheeks and jaws. All had recurrent skin infections, most by 3 months of age. All patients, except 1, had recurrent pneumonias, and most had recurrent bronchitis and otitis. Many patients developed pneumatoceles and most required chest tube drainage and/or lobectomies. Seven of the 13 had Candidal infections of the nails, vagina, or mouth. Three additional patients were described as having a 'variant' of the disorder due to lack of cold abscesses and serious sinopulmonary infection, declining serum IgE levels, and first appearance of infection at age 17 years, respectively. Laboratory studies showed mild to moderate eosinophilia. Impaired neutrophil chemotaxis was not a constant feature, and it was not severe when it occurred. There was some evidence for a chemotactic inhibitor. In patients with hyper-IgE syndrome, Dreskin et al. (1985) demonstrated deficiency of serum anti-Staph aureus IgA, salivary IgA, and salivary anti-Staph aureus IgA. There was an inverse correlation between the number of infections at mucosal surfaces and in adjacent lymph nodes and the levels of these substances as well as of total serum IgE and total serum IgD. Lui and Inculet (1990) described a patient with presumed Job syndrome and recurrent lung abscess necessitating lung resection. Serum IgE levels were markedly elevated. Some of the lung abscesses appeared to be due to Staph aureus; the resected right lower lobe showed an abscess cavity with aspergilloma. Borges et al. (1998) evaluated the facial features of 9 patients from 7 kindreds with Job syndrome. Consistent features included prominent forehead with deep-set eyes, increased width of the nose, a full lower lip, and thickening of the nose and ears. The mean alar width and outer canthal distance were significantly increased. The authors concluded that there is a recognizable face of Job syndrome. The study of Grimbacher et al. (1999) established that the hyper-IgE syndrome is a multisystem disorder. Grimbacher et al. (1999) studied 30 patients with hyper-IgE syndrome and 70 of their relatives. In addition to the recurrent skin and pulmonary abscesses and extremely elevated levels of IgE in serum, there are associated facial, dental, and skeletal features. Nonimmunologic features of the hyper-IgE syndrome were present in all patients older than 8 years. Failure or delay of shedding of the primary teeth owing to lack of root resorption was observed in 72%. Common findings among patients were recurrent fractures (57%), hyperextensible joints (68%), and scoliosis (in 76% of patients over 16 years of age). The classic triad of abscesses, pneumonia, and an elevated IgE level was identified in 77% of all patients and in 85% of those older than 8 years. In 6 (26%) of 23 adults, IgE levels declined over time and came closer to or fell within the normal range. Grimbacher et al. (1999) noted the unusual facial phenotype of the hyper-IgE syndrome, which had been commented on by Davis et al. (1966) and by Borges et al. (1998). By the age of 16 years, all of the patients studied by Grimbacher et al. (1999) showed distinctive facial characteristics, including facial asymmetry with a suggestion of hemihypertrophy, prominent forehead, deep-set eyes, broad nasal bridge, wide, fleshy nasal tip, and mild prognathism. The facial skin was rough, with prominent pores. The interalar distance was increased. Head circumference also tended to be larger than normal. PATHOGENESIS Milner et al. (2008) showed that interleukin-17 (IL17; see 603149) production by T cells is absent in individuals with hyper-IgE syndrome (HIES). They observed that ex vivo T cells from subjects with HIES failed to produce IL17, but not IL2 (147680), TNF (191160), or IFNG (147570), on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naive T cells were unable to differentiate into IL17-producing (TH17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gamma-t (602943), which is consistent with a crucial role for STAT3 (102582) signaling in the generation of TH17 cells. TH17 cells are an important subset of helper T cells that are believed to be critical in the clearance of fungal and extracellular bacterial infections. Thus, Milner et al. (2008) concluded that the inability to produce TH17 cells is a mechanism underlying the susceptibility to recurrent infections commonly seen in HIES. INHERITANCE Blum et al. (1977) reported hyper-IgE syndrome with recurrent severe Staphylococcal infections, eczematoid rash, and eosinophilia in 2 successive generations of a family. Buckley and Becker (1978) reviewed 20 patients with HIE syndrome. Since both males and females were affected in successive generations, they suggested autosomal dominant inheritance with incomplete penetrance. Leung and Geha (1988) reported 9 patients with the disorder. None of the patients had a family history of recurrent infections or consanguinity, indicating de novo or sporadic occurrence. Grimbacher et al. (1999) concluded that the hyper-IgE syndrome is inherited as an autosomal dominant disorder with variable expressivity. They presented pedigrees of 6 families, 4 of which had definitely affected cases in 2 successive generations. One family had affected father and son. Of 27 relatives at risk for inheriting the disorder, 10 were fully affected, 11 were unaffected, and 6 had combinations of mild immunologic, dental, and skeletal features of the hyper-IgE syndrome. DIAGNOSIS Leung and Geha (1988) reviewed cases of HIE syndrome and concluded that the most distinctive feature of the disorder is elevated serum IgE levels. They also emphasized the necessity to distinguish the HIE syndrome from atopic dermatitis (see, e.g., 603165), a disorder with which it is frequently confused. - Distinction from Atopic Dermatitis Grimbacher et al. (1999) noted several distinguishing features of HIE syndrome and severe atopic dermatitis. In HIE syndrome, Staphylococcus aureus infections are deep seeded and serious, non-Staph aureus infections are frequent, respiratory allergy is rare, and onset occurs between 1 and 8 weeks. In atopic dermatitis, Staphylococcus aureus infections are superficial and involve only the skin, non-Staph aureus infections are rare, respiratory allergy is common, and onset occurs after age 2 months. Patients with HIE often have coarse facies, which is not present in patients with atopic dermatitis. Severe atopic dermatitis is at least 10 times more common than HIE. CLINICAL MANAGEMENT In a prospective trial of levamisole in a large group of patients with Job syndrome, Donabedian et al. (1982) found no decrease in the propensity to infection, despite the fact that the drug clearly reversed the chemotactic defect. In a response to this report, Swim et al. (1982) suggested that the leukocyte defect and the proneness to infection in Job syndrome may be unrelated. MAPPING The finding of mutations in the STAT3 gene in patients with HIES (see MOLECULAR GENETICS) established that one form of the disorder maps to chromosome 17q21. - Genetic Heterogeneity Grimbacher et al. (1999) scored 19 kindreds with multiple cases of HIES for clinical and laboratory findings and genotyped the members of these 19 kindreds with polymorphic markers in a candidate region on chromosome 4. This region was selected because 1 patient with sporadic HIES plus autism and mental retardation was found to have a supernumerary marker chromosome, derived from a 15- to 20-cM interstitial deletion in 4q21. Linkage analysis in the 19 kindreds showed a maximum 2-point lod score of 3.61 at a recombination fraction of 0.0 with marker D4S428. Multipoint analysis and simulation testing confirmed that the proximal 4q region contains a disease locus for HIES. Six kindreds did not show linkage to 4q, indicating genetic heterogeneity. MOLECULAR GENETICS Minegishi et al. (2007) found that 8 of 15 unrelated nonfamilial HIES patients had heterozygous mutations in the STAT3 gene (see, e.g., 102582.0001-102582.0003). None of the parents or sibs of the patients had the mutant STAT3 allele, suggesting that these were de novo mutations. All 5 identified mutations were located in the DNA-binding domain of STAT3. The peripheral blood cells showed defective responses to cytokines, including interleukin-6 (IL6; 147620) and interleukin-10 (IL10; 124092), and the DNA-binding ability of STAT3 in these cells was greatly diminished. All 5 mutants were nonfunctional by themselves and showed dominant-negative effects when coexpressed with wildtype STAT3. Holland et al. (2007) collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokine secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated STAT3 as a candidate gene, which they then sequenced. They identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, 5 of which were hotspots, were predicted to affect directly the DNA-binding and SRC homology-2 (SH2) domains (see, e.g., 102582.0001-102582.0006). Renner et al. (2007) demonstrated that one of the original patients with Job syndrome described by Davis et al. (1966) had a heterozygous arg382-to-trp mutation (R382W; 102582.0002) in the STAT3 gene. NOMENCLATURE Davis et al. (1966) called the disorder 'Job syndrome' because of phenotypic similarity to the biblical figure Job: 'Satan...smote Job with sore boils from the sole of his foot unto his crown' (Job 2:7). HISTORY The first description of hyper-IgE syndrome (Davis et al., 1966) in girls with fair skin and red hair suggested an association with pigmentation. Later studies showed that the disorder is not associated with red hair or fair skin and that it occurs in both males and females (Donabedian and Gallin, 1983). Bannatyne et al. (1969) described 2 affected sisters whose parents were second cousins. Despite the fact that their parents were dark-skinned and dark-haired southern Italian immigrants, the proband had red hair, fair skin, and reddish-brown eyes. A sister was clinically well, but had red hair and a mild leukocyte defect demonstrated in vitro. Donabedian and Gallin (1983) concluded that the patients reported by Bannatyne et al. (1969) likely did not have HIES because neutrophils from those patients were unable to kill Staphylococci. Neutrophils isolated from patients with HIES do not show an inability to kill Staph bacteria. Witemeyer and Van Epps (1976) reported a brother and sister with defective cellular chemotaxis, recurrent infection, and red hair. However, neutrophil random mobility and bactericidal activity were normal, suggesting a different disorder. ► ▼ SQUAMOUS CELL CARCINOMA, HEAD AND NECK; HNSCC 275355 only shown in mice Lab: Beta family transforming growth factor resistance Inheritance: Autosomal recessive A number sign (#) is used with this entry because of evidence that a mutation of the TNFRSF10B gene (603612.0001), alone or in combination with other genes, can cause squamous cell carcinoma of the head and neck. Mutations in the ING1 gene (601566) have been found in a small but significant number of cases of squamous cell carcinoma of the head and neck. Somatic mutation in the PTEN gene (601728) has also been found in cases of HNSCC. PATHOGENESIS The transforming growth factor beta family of 25-kD polypeptides (TGFB1, 190180; TGFB2, 190220; TGFB3, 190230) are potent inhibitors of epithelial cell growth. Acquisition of cellular resistance to growth inhibitors, such as TGFB1, may represent an important step in tumor development. Human and murine epidermal keratinocytes secrete TGFB1, which appears to act as an autocrine inhibitor of growth. TGFB1 inhibits cell division by causing cells to arrest at the transition of G1 to S phase and stimulates keratinocyte differentiation. The acquisition of resistance to TGFB1 appears to represent an important step in the genesis of squamous cell carcinomas, as only transformed keratinocytes that have escaped from the negative control by TGFB1 seem to give rise to invasive carcinomas. Furthermore, most squamous carcinoma cell lines of the respiratory, digestive, and genital tracts are refractory to the antiproliferative action of TGFB1 in vitro. By use of somatic cell genetics, Reiss et al. (1993) studied the basis of the resistance of squamous carcinoma cell lines to TGFB1. Stable hybrid cell lines were obtained by fusing a TGFB1-resistant hypopharyngeal squamous carcinoma cell line with a papilloma virus 16-immortalized, TGFB1-sensitive, human foreskin keratinocyte cell line. TGFB1 type II receptor (TGFBR2; 190182) mRNA was detected in all sensitive and resistant cell lines studied. TGFB1 resistance of the squamous carcinoma cell line appeared to be recessive and due to the loss of 1 or more postreceptor elements of the signaling pathway. The gene encoding this (or these) element(s) may be located in the distal portion of chromosome 18q, as this was the sole chromosomal region of homozygous deletion in the resistant cell lines. Nawroz et al. (1996) stated that microsatellite DNA alterations are an integral part of neoplastic progression and there is evidence that senescent tumor cells release DNA into the circulation. The investigators reported results from PCR-based microsatellite analysis of paired samples of lymphocyte and serum DNA from 21 patients with primary head and neck squamous cell carcinoma. Microsatellite alterations were defined as the appearance of new alleles (new size forms) or loss of heterozygosity (LOH) at each of 12 markers, including IFNA (147660), CHRNB1 (100710), FGA (134820), and DRPLA (607462). Nawroz et al. (1996) reported that 6 out of 21 patients had 1 or more microsatellite alterations in serum that precisely matched the alteration in tumor DNA. All 6 patients had advanced disease and 5 patients had nodal metastases. The authors concluded that analysis of serum and plasma DNA may be useful for assessment of tumor burden, metastatic status, and overall prognosis. Koybasi et al. (2004) measured endogenous long-chain ceramides in 32 human HNSCC and 10 nonsquamous head and neck carcinoma tumor tissues, and found that C(18:0)-ceramide was selectively downregulated in the majority of HNSCC tumor tissues but not in the nonsquamous tumor tissues or in adjacent noncancerous tissues from HNSCC patients. Overexpression of the homolog of S. cerevisiae lag1 gene (LASS1; 606919) in an HNSCC cell line resulted in a 2-fold increase in levels of C(18:0)-ceramid e to concentrations similar to those of normal head and neck tissues and was associated with a 70 to 80% inhibition of cell growth. Koybasi et al. (2004) concluded that LASS1 and C(18:0)-ceramide have a biologic role in the regulation of growth of head and neck squamous cell carcinomas. DIAGNOSIS Roepman et al. (2005) showed that DNA microarray gene expression profiling can detect lymph node metastases for primary head and neck squamous cell carcinomas that arise in the oral cavity and oropharnyx. The predictor, established with a set of 82 tumors, outperformed current clinical diagnosis when independently validated. The 102 predictor genes offered unique insight into the processes underlying metastasis. The results showed that the metastatic state can be deciphered from the primary tumor gene expression pattern and that treatment can be substantially improved. MAPPING - Immortality of Squamous Cell Carcinoma Most advanced squamous cell carcinomas are immortal. Forsyth et al. (2002) noted that analyses of the immortal phenotype had shown several genetic alterations to be important to the process, including dysfunction of p53 (191170), INK4A (600160), and a gene on chromosome 3p that represses telomerase activity. LOH of other chromosomes, including chromosome 4, had also been observed. To test for a functional cancer mortality gene on chromosome 4, Forsyth et al. (2002) introduced a complete or fragmented copy of the chromosome into squamous cell carcinoma cell lines by microcell-mediated chromosome transfer (MMCT). In those lines with LOH on chromosome 4, the process caused a delayed crisis, but chromosomes 3, 6, 11, and 15 were without effect. MMCT of chromosomal fragments into BICR6 mapped the mortality gene to the region 4cen-q23. Mutation analysis of the introduced chromosome in immortal segregants narrowed the candidate interval to 2.7 Mb spanning the markers D4S423 and D4S1557. The results suggested the existence of a gene on chromosome 4 whose dysfunction contributes to the continuous proliferation of squamous cell carcinomas and indicated that this gene operates independently of telomeres, p53, and INK4A. MOLECULAR GENETICS - Mutation in the TNFRSF10B Gene Pai et al. (1998) performed sequence analysis of all 10 coding exons of the TNFRSF10B gene (603612.0001) in 20 primary head and neck cancers with allelic loss of 8p. To screen for a subset of mutations localized to the functional cytoplasmic death domain, they sequenced this region in an additional 40 primary head and neck cancers. They found 2 alterations, including a 2-bp insertion at a minimal repeat site (603612.0001), introducing a premature stop codon and resulting in a truncated protein. Sequence analysis of normal tissue from the patient showed that the truncating mutation was also present in the germline, and that the tumor did not have a p53 mutation. - Mutation in the ING1 Gene In tumor tissue of squamous cell carcinoma of the head and neck, Gunduz et al. (2000) identified missense mutations in the ING1 gene (see, for example, 601566.0001). - Mutation in the PTEN Gene In a study of 52 HNSCC tumor samples, Poetsch et al. (2002) found an ala121-to-gly mutation (A121G; 601728.0031) in the PTEN gene in 1 oropharyngeal and 1 laryngeal carcinoma. - Role of MicroRNAs Cervigne et al. (2009) examined microRNA (miR) expression changes in 43 sequential progressive oral leukoplakia samples from 12 patients and 4 nonprogressive leukoplakias from 4 different patients. The findings were validated using quantitative RT-PCR in an independent cohort of 52 progressive dysplasias and oral squamous cell carcinomas (OSCCs), and 5 nonprogressive dysplasias. Global miR expression profiles distinguished progressive leukoplakia/OSCC from nonprogressive leukoplakias/normal tissues. Of 109 miRs which were highly expressed exclusively in progressive leukoplakia and invasive OSCC, miR21 (611020), miR181b (612744), and miR345 expression was consistently increased and associated with increases in lesion severity during progression. The authors hypothesized that overexpression of miR21, miR181b, and miR345 may play an important role in malignant transformation. ► ▼ PROSTATE CANCER 176807 only shown in mice Oncology: Early onset prostate cancer Inheritance: Autosomal dominant form A number sign (#) is used with this entry because of evidence that several genes are involved in the origin and/or progression of this neoplasm: hereditary prostate cancer-1 (HPC1; 601518) on 1q25, MAX-interacting protein-1 (MXI1; 600020) on 10q, and KAI1 prostate cancer antimetastasis gene (KAI1; 600623) on 11p. Point mutations in the MXI1 gene have been observed in prostate tumors (e.g., 600020.0001). A predisposing locus for early-onset prostate cancer (HPC8; 602759) has been assigned to 1q42.2-q43, at a distance from the HPC1 locus. A prostate cancer susceptibility locus on Xq27-q28 (HPCX1; 300147) and a prostate cancer/brain cancer susceptibility locus on 1p36 (CAPB; 603688) have been proposed. An additional susceptibility locus on the X chromosome exists, on Xp11.22 (HPCX2; 300704). A gene on 17p, HPC2/ELAC2 (605367), had also been identified, harboring mutations that segregate with prostate cancer. Several loci for hereditary prostate cancer have been mapped: HPC3 (608656) on chromosome 20q13, HPC4 (608658) on chromosome 7q11-q21, HPC5 (609299) on chromosome 3p26, HPC6 (609558) on chromosome 22q12, HPC7 (610321) on chromosome 15q12, and HPC9 (610997) on chromosome 17q21-q22. Strong association with multiple independent variants on chromosome 8q24 has been found and replicated (HPC10: 611100). Polymorphisms in the HNF1B gene (189907) have been associated with susceptibility to prostate cancer (HPC11; see 611955). Additionally, loci on chromosomes 2p15 (HPC12, 611868, associated with polymorphism in EHBP1, 609922), 10q11.2 (HPC13, 611928, associated with polymorphism in MSMB, 157145), 11q13 (HPC14; 611958), and 19q13.4 (HPC15; 611959) have been identified. Somatic mutations in the PTEN gene (601728), the MAD1L1 gene (602686), the ATBF1 gene (ZFHX3; 104155), and the PLXNB1 gene (601053) have been identified in prostate cancer tumors (see 601728.0018, 602686.0002, and 104155.0001, respectively). The HUGO Nomenclature Committee assigned the symbol PRCA1 (601518) for hereditary prostate cancer that maps to 1q24-q25, based on a study by Carter et al. (1992). Carpten et al. (2002) related the locus on 1q24-q25 to 2 germline mutations in the ribonuclease L gene (180435). Loss of KLF6 (602053) function is also implicated in prostate cancer. Mutations in the gene encoding macrophage scavenger receptor-1 (153622) have been identified in both hereditary and nonhereditary prostate cancer. Mutations in the CHEK2 gene (604373), which have been associated with non-p53-based Li-Fraumeni syndrome (LFS2; 609265), have also been identified in hereditary and nonhereditary prostate cancer (see, e.g., 604373.0007; 604373.0011-604373.0013). Mutational inactivation of the EPHB2 gene (600997) has been implicated in the progression and metastasis of prostate cancer. A promoter polymorphism (192090.0018) in the CDH1 gene has been associated with risk of hereditary prostate cancer. Studies by Woolf (1960), Cannon et al. (1982), Meikle et al. (1985) and others suggested the significance of familial factors in prostate cancer. The aggressiveness of prostate cancer varies widely. Some tumors progress to invasive, potentially life-threatening disease, whereas others stay latent for the remainder of an individual's lifetime. Silverberg (1986) stated that in American men, prostate cancer is the most common malignancy and the second most common cause of cancer deaths. Over 100,000 cases of prostate cancer had occurred annually in the United States in previous years, with 20,000 of these cases occurring in men under the age of 65 years. Seidman et al. (1985) estimated that 9% of white males and 10% of black males in the U. S. will develop clinical prostate cancer in their lifetime. Steinberg et al. (1990) investigated the frequency of prostate cancer in the relatives of 691 men with prostate cancer and 640 of their spouses. In 15% of the cases, but only 8% of the controls, it was a father or brother affected with prostate cancer (P less than 0.001). Men with a father or brother affected were twice as likely to develop prostate cancer as men with no relatives affected. There was a trend of increasing risk with increasing number of affected family members, such that men with 2 or 3 first-degree relatives affected had a 5- and 11-fold increased risk of developing prostate cancer, respectively. Carter et al. (1992) found in the 691 prostate cancer families that early onset of disease in the proband was also an important determinant of risk. Complex segregation analysis led to the conclusion that the family clustering was best explained by autosomal dominant inheritance of a rare (q = 0.0030) high-risk allele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer for carriers showed that the allele was highly penetrant; by age 85, 88% of carriers compared to only 5% of noncarriers were projected to be affected with prostate cancer. Twin studies support the existence of a significant genetic factor (Walsh, 1992). To determine whether family history is associated with an increased prevalence of prostate cancer in an unselected group of men attending a hospital-based screening clinic, Narod et al. (1995) inquired about affected relatives before prostate cancer screening in 6,390 men, aged 50 to 80 years, in the region of Quebec City. Of these 6,390 men, 1,563 (24.5%) had a positive test by either rectal examination or blood test for prostate-specific antigen (APS; 176820). Among the 6,390 men, 264 were found to have prostate cancer (4.13%). The prevalence was increased in those men with any first-degree relative affected (prevalence = 6.7%; relative risk = 1.72 as compared with men with no first-degree relative affected; prevalence = 3.89; relative risk = 1.00). Most of the increase in relative risk was contributed by affected brothers (prevalence = 10.2%; relative risk = 2.62; P = 0.0002). Schaid et al. (1998) performed a family history cancer survey on 5,486 men who underwent radical prostatectomy at the Mayo Clinic for clinically localized prostate cancer; 4,288 men responded to the survey. The best-fitting model that explained familial aggregation was a rare autosomal dominant susceptibility gene, and this model fit best when probands were diagnosed under 60 years of age. The model predicted that the frequency of a susceptibility gene in the population is 0.006 and that the risk of prostate cancer by age 85 years is 89% among carriers of the gene and 3% among noncarriers. Genetic heterogeneity was suggested by the study. Other evidence suggesting genetic complexity included the significantly elevated age-adjusted risk of prostate cancer among brothers of probands, compared with their fathers. Nieder et al. (2003) suggested that major risk factors for developing prostate cancer, including positive family history and African American ethnicity, can be quantified for genetic counseling. Factors increasing familial risk for prostate cancer are closer degree of kinship, number of affected relatives, and early age of onset (under 50 years) among the affected relatives. Genetic testing may be useful for modification of risk, but at the time of writing, Nieder et al. (2003) suggested that genetic testing should be performed only within the context of a well-designed research study that will determine penetrance and genotype-phenotype correlation of specific mutations. Even in the absence of genetic testing, African American men and men with a strong family history of prostate cancer may opt to initiate screening by prostate-specific antigen and digital rectal examination at age 40 years. Cui et al. (2001) conducted single- and 2-locus segregation analyses of data from 1,476 men with prostate cancer diagnosed under the age of 70 years and ascertained through population registers in Australia, together with brothers, fathers, and both maternal and paternal lineal uncles. All 2-locus models gave better fits than did single-locus models, even if lineal uncles were excluded. The best-fitting genetic models included a dominantly inherited increased risk that was greater, in multiplicative terms, at younger ages, as well as a recessively inherited or X-linked increased risk that was greater, in multiplicative terms, at older ages. Penetrance to age 80 years was approximately 70% for the dominant effect and virtually 100% for the recessive and X-linked effects. Both genetic and environmental influences are probably involved in the variability of prostate cancer aggressiveness. To investigate genetic factors, Witte et al. (2000) conducted a genomewide linkage analysis of 513 brothers with prostate cancer, using the Gleason score, which reflects tumor histology, as a quantitative measure of prostate cancer aggressiveness. To their knowledge, this was the first time that a measure of prostate cancer aggressiveness had been directly investigated as a quantitative trait in a genomewide scan. Candidate regions were found on 5q, 7q, and 19q. Slager et al. (2003) analyzed genome scan data from 161 pedigrees affected with prostate cancer using the Gleason score as a quantitative measure of tumor aggressiveness. Their results confirmed the assignment of a prostate cancer aggressiveness quantitative trail locus to chromosome 19q (607592). In addition, they reported suggestive evidence for linkage to chromosome 4. Gibbs et al. (2000) also found evidence of linkage at multiple sites in a genome scan. Stratification by a variety of factors appeared to improve the chances of identifying relevant genes. Xu et al. (2001) undertook a systematic evaluation of linkage across chromosome 1 using 50 microsatellite markers in 159 hereditary prostate cancer families, including 79 families analyzed in the original report by Smith et al. (1996) describing HPC1 linkage. The results of the new study were consistent with the heterogeneous nature of hereditary prostate cancer and the existence of multiple loci on chromosome 1 for this disease. Berry et al. (2000) found evidence for a prostate cancer susceptibility locus on 20q13 (HPC3; 608656), particularly in families having less than 5 affected members, a later average age of diagnosis, and no male-to-male transmission. To further assess the potential contribution of a 20q13 locus to prostate cancer susceptibility, Bock et al. (2001) studied 172 unrelated families affected by prostate cancer, using 17 polymorphic markers across a 98.5-cM segment of chromosome 20 that contains the candidate region. The strongest evidence for linkage was seen in a subset of 16 black families, but in general the linkage study did not provide statistically significant support for the existence of a prostate cancer-susceptibility locus at 20q13. On the other hand, Zheng et al. (2001) found elevated nonparametric linkage (NPL) scores in a study of 159 hereditary prostate cancer families and higher NPL scores in subsets of families with a later age of diagnosis (65 years or later), fewer than 5 affected family members, or no male-to-male disease transmission. Ichikawa et al. (1991) and Ichikawa et al. (1992) demonstrated that somatic cell hybridization of nonmetastatic rat prostate cancer cells with highly metastatic rat prostate cancer cells resulted in suppression of metastatic potential, although the cell hybrids remained tumorigenic. They also showed that the 11p11.2 region of the human genome contains a gene that suppresses metastasis as indicated by the results of microcell-mediated chromosome transfer. Dong et al. (1995) isolated the 11p11.2 gene, which they designated KAI1. Eagle et al. (1995) demonstrated that mutation in the MXI1 gene is involved in either the pathogenesis or the neoplastic evolution of some prostate cancer. The MXI1 protein negatively regulated MYC oncoprotein (190080) activity and thus potentially serves a tumor suppressor function. Furthermore, MXI1 maps to chromosome 10q25, a region that is deleted in some cases of prostate cancer. Eagle et al. (1995) detected mutations in the retained MXI1 allele in 4 primary prostate tumors with 10q24-q25 deletions, thus satisfying the Knudson hypothesis. In Los Angeles County, California, prostate cancer incidence differs considerably among the various racial-ethnic groups: highest in African Americans (116 per 1,000 person-years), intermediate in non-Hispanic whites (71 per 100,000 person-years), and lowest among Asians (Japanese at 39 per 100,000 person-years and Chinese at 28 per 100,000 person-years). One of the critical functions of the product of the androgen receptor gene (AR; 313700) is to activate the expression of target genes. This transactivation activity resides in the N-terminal domain of the protein, which is encoded in exon 1 and contains polymorphic CAG and GGC repeats (microsatellites). A smaller size of the CAG repeat is associated with a higher level of receptor transactivation function, thereby possibly resulting in a higher risk of prostate cancer. Schoenberg et al. (1994) demonstrated contraction in this microsatellite from 24 to 18 CAG units in an adenocarcinoma of the prostate, and the affects of the shorter allele were implicated in the development of the tumor. Edwards et al. (1992) and Irvine et al. (1995) showed that the prevalence of short CAG alleles was highest in African American males with the highest risk for prostate cancer, intermediate in intermediate-risk non-Hispanic whites, and lowest in Asians at very low risk for prostate cancer. Irvine et al. (1995) found that high-risk African Americans also had the lowest frequency of the GGC allele. Consistent with the interracial variation in CAG and GGC distributions, there was an excess of white patients with short CAG repeats relative to white controls. Irvine et al. (1995) found a statistically significant negative association between the number of CAG and GGC repeats among the prostate cancer patients. Overall, the data were interpreted to suggest a possible association between the microsatellites of the AR gene and the development of prostate cancer. In the Ashkenazi-Jewish population, 3 founder mutations, 185delAG (113705.0003) and 5382insC (113705.0018) in the BRCA1 gene and 6174delT (600185.0018) in the BRCA2 gene, exist at a relatively high frequency as predisposing mutations for breast cancer and ovarian cancer. Hubert et al. (1999) reasoned that if germinal mutations in the BRCA1 and BRCA2 genes increased the risk of prostate cancer in carriers, it would be expected that the carrier frequency in prostate cancer patients would be higher than in the general population, as documented in female patients diagnosed with breast cancer and ovarian cancer. However, they found no evidence for an increased frequency of prostate cancer in association with these mutations in Ashkenazi males. Ostrander and Stanford (2000) reviewed the search for prostate cancer genes. Peters and Ostrander (2001) presented a tabulation of the cytogenetic location of 16 mapped prostate cancer susceptibility loci and candidate genes. Oba et al. (2001) studied the significance of the loss of heterozygosity (LOH) frequently observed on chromosome 8p in prostate cancer. By fluorescence in situ hybridization (FISH) in 42 prostate cancers, they found a deletion for at least 1 locus on 8p in 29 (69%) tumors. A significantly higher frequency of the deletion on 8p21.2-p21.1 was observed in advanced prostate cancer than in localized prostate cancer. They concluded that deletions on 8p22-p21.3 play an important role in tumor differentiation, while 8p21.2-p21.1 deletion plays a role in progression of prostate cancer. Xu et al. (2001) performed linkage analysis using 24 markers from 8p in 159 pedigrees with hereditary prostate cancer. In 79 families with an average age at diagnosis of greater than 65 years, an allele-sharing lod score of 2.64 (P = 0.0005) was observed. Of note, the small number (11) of Ashkenazi Jewish pedigrees analyzed in this study contributed disproportionately to this linkage. Mutation screening in hereditary prostate cancer probands and association analyses in case subjects and unaffected control subjects was carried out for a putative prostate cancer susceptibility gene, which they called PG1, previously localized to the 8p22-p23 region. (PG1 had been cloned in a haplotype-based association study conducted by Geneset by Daniel Cohen and described only in a US patent dated August 31, 1999.) Xu et al. (2001) concluded that evaluation of PG1 and other candidate genes in the region appeared warranted. Goddard et al. (2001) detected linkage near 3 locations for prostate cancer: 1q24-q25 (HPC1), 1q42.2-q43 (HPC8), and near Xq12-q13, the AR locus. Six other locations gave lod scores greater than 2.5. Cancel-Tassin et al. (2001) examined evidence for linkage to the HPC1, HPC8, CAPB, and HPCX loci in 64 families from southern and western Europe with at least 3 affected individuals with prostate cancer. No significant evidence of linkage to HPC1, CAPB, or HPCX was found. Results in favor of linkage to HPC8 were observed and homogeneity analysis gave an estimated proportion of families with linkage to this locus up to 50%. Using cDNA microarrays, Dhanasekaran et al. (2001) examined gene expression profiles of more than 50 normal and neoplastic prostate specimens and 3 common prostate cancer cell lines. Signature expression profiles of normal adjacent prostate, benign prostatic hypertrophy, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Dhanasekaran et al. (2001) established many associations between genes and prostate cancer. They assessed 2 of these genes, hepsin (142440), a transmembrane serine protease, and PIM1 (164960), a serine/threonine kinase, at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate cancer specimens. Expression of hepsin and PIM1 proteins was significantly correlated with measures of clinical outcome. Green tea, a popular beverage consumed worldwide, has been shown to possess cancer chemopreventive effects in a wide range of target organs in rodent carcinogenesis models. The effects have been attributed to the biochemical and pharmacologic activities of its polyphenolic constituents. Epidemiologic studies, although inconclusive, suggest a protective effect on some cancer types in humans. People who consume tea regularly may have a lower risk of prostate cancer. The Japanese and Chinese populations who regularly consume tea, especially green tea, have one of the lowest incidences of prostate cancer in the world. Gupta et al. (2001) used the TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse as a model for testing the effect of green tea in this cancer. In this model, expression of the SV40 early genes are driven by the prostate-specific promoter probasin that leads to cell transformation within the prostate. One-hundred percent of male TRAMP mice develop cancer of the prostate without any chemical or hormonal treatment. Gupta et al. (2001) found that oral infusion of a polyphenolic fraction isolated from green tea causes significant inhibition in the development, progression, and metastasis of prostate cancer to distant organ sites in these mice. Narla et al. (2001) identified loss of heterozygosity of 1 KLF6 allele in 77% of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. Functional studies confirmed that whereas wildtype KLF6 upregulates p21 (WAF1/CIP1; 116899) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. See 600020 for discussion of a locus on chromosome 10q25 that may be associated with prostate cancer. Valeri et al. (2003) stated that recent linkage analyses had led to the detection of at least 8 prostate cancer predisposing genes, suggesting complex inheritance and genetic heterogeneity. They conducted segregation analysis in 691 prostate cancer patients, recruited from 3 French hospitals and unselected with respect to age at diagnosis, clinical stage, or family history. Segregation analyses were carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts. Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency 0.03%) with an additional brother-brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at-risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. The study supported the model of mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrated that additional genetic and/or common sib environmental factors are involved to account for the familial clustering of prostate cancer. In 940 Ashkenazi Israelis with prostate cancer, Giusti et al. (2003) tested DNA obtained from paraffin sections for the 3 Jewish founder mutations: 185delAG (113705.0003) and 5382insC (113705.0018) in BRCA1 and 6174delT (600185.0009) in BRCA2. They estimated that there is a 2-fold increase in BRCA mutation-related prostate cancer among Ashkenazi Israelis. No differences were noted between the histopathologic features of cases with or without founder mutations, and no difference was found in the mean age at diagnosis between cases with or without a founder mutation. To explore potential molecular variation underlying the broad range of clinical behavior of prostate cancer from relatively indolent to aggressive metastatic disease, Lapointe et al. (2004) profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and 9 lymph node metastases, using cDNA microarrays containing approximately 26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified 3 subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among 2 of the 3 subtypes, 1 of which also included most lymph node metastases. To characterize further the clinical relevance of tumor subtypes, Lapointe et al. (2004) evaluated as surrogate markers 2 genes differentially expressed among tumor subgroups using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1 (158340), a gene highly expressed in the 2 subgroups with 'aggressive' clinicopathologic features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1 (194460), a gene highly expressed in the third subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative levels of prostate-specific antigen (PSA; 176820). The results suggested that prostate tumors can be classified according to their gene expression patterns. Nam et al. (2001) investigated the val89-to-leu polymorphism (V89L) of the SRD5A2 gene (607306) in 320 men undergoing evaluation for prostate cancer, and found that the adjusted odds ratio for having prostate cancer for men with at least 1 V allele was 2.53 compared to men with the L/L genotype (95% CI, 1.11-5.78; p = 0.03). When stratified for ethnic background, the effect of the V89L polymorphism did not vary among whites, blacks, and Asians. In a separate cohort of 318 men with known prostate cancer, Nam et al. (2001) found that the odds ratio for progression for men with at least 1 V allele was 3.32 compared to men with the L/L genotype (95% CI, 1.67-6.62; p = 0.0006). In a genotype/haplotype association study involving a case-control sample of 1,117 brothers from 506 sibships with prostate cancer, Loukola et al. (2004) detected positive associations between prostate cancer risk and 2 single-nucleotide polymorphisms (SNPs) in SRD5A2 (V89L and -3001G-A) and observed an inverse association between high aggressiveness of prostate cancer and SRD5A2_Hap3. The authors could not confirm a previously reported association between prostate cancer and the SRD5A2 A49T polymorphism (607306.0012). Loukola et al. (2004) also detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 (124010) SNPs and a CYP3A4 haplotype; they noted that both the CYP3A41B allele and the CYP3A4_Hap4 haplotype were inversely associated with low disease aggressiveness. Schaid et al. (2004) compared genome linkage scans for prostate cancer susceptibility loci using microsatellites with those using SNPs, performed in 467 men with prostate cancer from 167 families. The highest lod scores were found for chromosome 6 (4.2) and chromosome 12 (3.9), but these were judged difficult to interpret because they occurred only at the extreme ends of the chromosomes. The greatest gain provided by the SNP markers was a large increase in the linkage information content, with an average information content of 61% for the SNPs versus an average of 41% for the microsatellite markers. Paris et al. (2004) analyzed a cohort of 64 prostate cancer patients (half of whom had postoperative recurrence) using array comparative genomic hybridization (aCGH). Analysis of the aCGH profiles revealed numerous recurrent genomic copy number aberrations. Specific loss at 8p23.2 was associated with advanced stage disease, and gain at 11q13.1 was found to be predictive of postoperative recurrence independent of stage and grade. Moreover, comparison with an independent set of metastases revealed approximately 40 candidate markers associated with metastatic potential. The authors proposed that copy number aberrations at these loci may define metastatic genotypes. Karhadkar et al. (2004) found that activity of the hedgehog (see 600725) signaling pathway, which has essential roles in developmental patterning, was required for regeneration of prostate epithelium, and that continuous pathway activation transformed prostate progenitor cells and rendered them tumorigenic. Elevated pathway activity furthermore distinguished metastatic from localized prostate cancer, and pathway manipulation modulated invasiveness and metastasis. Pathway activity was triggered in response to endogenous expression of hedgehog ligands, and was dependent upon the expression of Smoothened (601500), which is not expressed in benign prostate epithelial cells. Karhadkar et al. (2004) concluded that monitoring and manipulating hedgehog pathway activity may offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential. Chang et al. (2004) analyzed the CDKN1B gene (600778) in 188 families with hereditary prostate cancer and found a significant association between the SNP -79C/T (dbSNP rs34330) and prostate cancer. The -79C allele was overtransmitted from parents to affected offspring, an association that was observed primarily in offspring whose age at diagnosis was less than 65 years. Chang et al. (2004) suggested that germline variants of this gene play a role in prostate cancer susceptibility. In a Swedish population, Jonsson et al. (2004) demonstrated an association between the -160C/A promoter polymorphism in the CDH1 gene (192090.0018) and risk of hereditary prostate cancer. In an independent replication study population, Lindstrom et al. (2005) confirmed the association. Seligson et al. (2005) used immunohistochemical staining of primary prostatectomy tissue samples to determine the percentage of cells that stained for the histone acetylation and dimethylation of 5 residues in histones H3 (see 142780) and H4 (see 602824). Grouping of samples with similar patterns of modifications identified 2 disease subtypes with distinct risks of tumor recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumor stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, Seligson et al. (2005) concluded that widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behavior in cancer patients. Xu et al. (2005) performed genomewide linkage analysis of 269 prostate cancer families with at least 5 affected members and found significant linkage at 22q12 (lod score, 3.57; HPC6; 609558). They also found 'suggestive' linkage (lod score of 1.86 or greater) at 1q25, 8q13, 13q14, 16p13, and 17q21 (HPC9; 610997) in these families. In 606 families with prostate cancer with a mean age at diagnosis of 65 years or less, 4 additional suggestive linkages were found: 3p24, 5q35, 11q22, and Xq12. Tomlins et al. (2005) used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG (165080) and ETV1 (600541), were identified as outliers in prostate cancer. Tomlins et al. (2005) identified recurrent gene fusions of the 5-prime untranslated region of TMPRSS2 (602060) to ERG or ETV1 in prostate cancer tissues with outlier expression. By using FISH, Tomlins et al. (2005) demonstrated that 23 of 29 prostate cancer samples harbored rearrangements in ERG or ETV1. Cell line experiments suggested that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer. Tomlins et al. (2007) explored the mechanism of ETV1 outlier expression in human prostate tumors and prostate cancer cell lines. They identified previously unknown 5-prime fusion partners in prostate tumors with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3; 605097) and an endogenous retroviral element, HERV-K_22q11.23), a prostate-specific androgen-repressed gene (C15ORF21; 611314), and a strongly expressed housekeeping gene (HNRNPA2B1; 600124). To study aberrant activation of ETV1, Tomlins et al. (2007) identified 2 prostate cancer cell lines that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-Mb prostate-specific region at 14q13.3-q21.1 in both cell lines, in one by cryptic insertion and in the other by balanced translocation. Because the common factor of these rearrangements is aberrant ETV1 overexpression, Tomlins et al. (2007) recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrated that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci. Chang et al. (2006) performed 2-locus conditional linkage analysis to identify possible gene-gene interactions in a genomewide scan of 426 families with prostate cancer. Suggestive evidence for an epistatic interaction was found for 6 sets of loci: 11q13 and 13q32; 22q13 and 21q22; 12q24 and 16p13; 8q24 and 7q21; 20p13 and 16q21; and 5p13 and 16p12. Luo et al. (2007) examined IKK-alpha (CHUK; 600664) involvement in prostate cancer and its progression. They demonstrated that a mutation that prevents IKK-alpha activation slowed down prostate cancer growth and inhibited metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin (154790), the ablation of which restored metastatic activity. IKK-alpha activation by RANK ligand (RANKL; 602642) inhibited Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription required nuclear translocation of active IKK-alpha. The amount of active nuclear IKK-alpha in mouse and human prostate cancer correlated with metastatic progression, reduced Maspin expression, and infiltration of prostate tumors with RANKL-expressing inflammatory cells. Luo et al. (2007) proposed that tumor-infiltrating RANKL-expressing cells lead to nuclear IKK-alpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype. Pakkanen et al. (2007) performed segregation analysis in 2 cohorts of 557 early-onset and 989 late-onset nuclear Finnish families in which the father had histologically confirmed prostate cancer. Their findings suggested that inheritance of prostate cancer in the Finnish population is best explained by a mendelian recessive model with a significant paternal regressive coefficient that is indicative of a polygenic multifactorial component. Gudmundsson et al. (2007) performed a genomewide association scan of 1,501 Icelandic men with prostate cancer and 11,290 controls, followed by 3 case-control replication studies in individuals from the Netherlands, Spain, and Chicago. They found an association between 2 SNPs on chromosome 17q with prostate cancer: the A allele of dbSNP rs4430796 in intron 2 of the HNF1B gene (189907) at chromosome 17q12 (see HPC11, 611955) and the G allele of dbSNP rs1859962 at chromosome 17q24.3 (p = 1.4 x 10(-11) and p = 2.5 x 10(-10), respectively, for the combined studies). The SNPs were outside the 10-cM candidate gene region (HPC9; 610997) proposed by Lange et al. (2007) but within a region with suggestive LOD scores. Gudmundsson et al. (2007) noted that the risks conferred by these variants are modest (allele odds ratio of about 1.20), but because they are common their joint population-attributable risk is substantial (approximately 36%). In a screen for endogenous tumor-associated T-cell responses in a primary mouse model of prostatic adenocarcinoma, Savage et al. (2008) identified a naturally arising CD8+ (186910) T cell response that is reactive to a peptide derived from histone H4 (602822). Despite the ubiquitous nature of histones, T cell recognition of histone H4 peptide was specifically associated with the presence of prostate cancer in these mice. Thus, Savage et al. (2008) concluded that the repertoire of antigens recognized by tumor-infiltrating T cells is broader than previously thought and includes peptides derived from ubiquitous self antigens that are normally sequestered from immune detection. Gudmundsson et al. (2008) conducted a genomewide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: dbSNP rs5945572 on Xp11.22 (HPCX2; 300704) and dbSNP rs721048 on 2p15 (HPC12; 611868); odds ratios (OR) = 1.23 and 1.15, respectively. The 2p15 variant, within an intron of the EHBP1 gene (609922), showed a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease. Thomas et al. (2008), in a genomewide association study (GWAS) of prostate cancer, confirmed 3 previously reported loci: 2 independent SNPs at 8q24 (HPC10; 611100) and 1 in HNF1B (189907) on 17q (HPC11; 611955). In addition, loci on chromosomes 7, 10 (2 loci), and 11 (HPC14; 611958) were highly significant. Loci on chromosome 10 (see HPC13, 611928) included MSMB (175145), which encodes beta-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2 (602619), a gene with antiapoptotic activity. The locus on chromosome 7 was at JAZF1 (606246), a transcriptional repressor that is fused by chromosome translocation to SUZ12 (606245) in endometrial cancer. Of the 9 loci that showed highly suggestive associations, 4 best fit a recessive model and included candidate susceptibility genes: CPNE3 (604207), IL16 (603035), and CDH13 (601364). The findings pointed to multiple loci with moderate affects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals. Eeles et al. (2008) conducted a genomewide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA; 176820) concentration (less than 0.5 ng/ml). They analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. They identified 7 loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11 (HPC14), 19 (HPC15; 611959), and X. They confirmed previous reports of common loci associated with prostate cancer at 8q24 (HPC10; 611100) and 17q (HPC11; 611955). Three of the newly identified loci contained candidate susceptibility genes: MSMB (157145) on 10q11.2, LMTK2 (610989) on 7q21.3-q22.1 (see also HPC4, 608658), and KLK3 (176820) on 19q13.4. Using a combination of high-throughput liquid and gas chromatography-based mass spectrometry, Sreekumar et al. (2009) profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer, and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that is highly increased during prostate cancer progression to metastasis and can be detected noninvasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase (606628), the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase (604455), induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor (AR; 313700) and the ERG gene fusion product (see 165080) coordinately regulate components of the sarcosine pathway. Sreekumar et al. (2009) concluded that by profiling the metabolomic alterations of prostate cancer progression, they revealed sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity. Using dual-color FISH in LNCaP prostate cancer cells, which are androgen-sensitive but lack the TMPRSS2-ERG fusion gene, Mani et al. (2009) observed that stimulation with the AR ligand dihydrotestosterone (DHT) for 60 minutes induced proximity between the TMPRSS2 and ERG genomic loci. The effect was dependent upon AR, as the same proximity was not induced in an androgen-insensitive prostate cancer cell line. To determine whether the induced proximity facilitates formation of these gene fusions, Mani et al. (2009) treated LNCaP cells with DHT for 12 hours and then irradiated the cells to induce DNA double-strand breaks. TMPRSS2-ERG fusions were detected in 25% of clones treated with 3-Gy irradiation but in only 2.3% of those treated with 1-Gy. Mani et al. (2009) speculated that androgen signaling colocalizes the 5- and 3-prime gene fusion partners, thereby increasing the probability of a gene fusion when subjected to agents that cause DNA double-strand breaks. Gudmundsson et al. (2009) reported a prostate cancer genomewide association follow-up study and discovered 4 variants associated with susceptibility to prostate cancer in several European populations: dbSNP rs10934853A (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; 2 SNPs on chromosome 8q24.21, as described in HPC10 (611100); and dbSNP rs8102476C (odds ratio = 1.12, P = 1.6 x 10(-11)) on 19q13.2. Gudmundsson et al. (2009) also refined a previous association signal on 11q13 (see HPC14, 611958). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, Gudmundsson et al. (2009) estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population. Eeles et al. (2009) extended the study of Eeles et al. (2008) to evaluate promising associations in a second stage in which they genotyped 43,671 SNPs in 3,650 prostate cancer cases and 3,940 controls, and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, Eeles et al. (2009) identified 7 new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)). The strongest association was found with a G/A SNP at chromosome 11p15, dbSNP rs7127900 (position 2,190,150; per-allele OR = 1.22, 95% CI = 1.17-1.27, P = 2.7 x 10(-33)). The TMPRS22 and ERG genes are arranged tandemly on chromosome 21q22. The TMPRSS2/ERG fusion joins TMPRSS2 exons 1 or 2 usually to ERG exons 2, 3 or 4, which results in activation of the ERG transcription factor. This fusion separates the ERG 3-prime centromeric regions from the 5-prime telomeric ends; deletions of this region can also occur. Attard et al. (2008) performed FISH studies of the TMPRS22/ERG genes in 445 prostate cancers from patients who had been managed conservatively. The authors identified an alteration, called 2+Edel, characterized by duplication of the TMPRS22/ERG fusion (detected as duplication of 3-prime ERG sequence) together with interstitial deletion of 5-prime ERG sequences. The alteration was found in 6.6% of cancers and was associated with very poor clinical outcome compared to cancers with normal ERG loci (25% vs 90% survival at 8 years). Cancers with 1 copy of 3-prime ERG (1Edel) did not have a worse clinical outcome. The findings were consistent with the hypothesis that overexpression of ERG that results from the fusion of 5-prime TMPRSS2 to 3-prime ERG is responsible for driving cancer progression. Attard et al. (2008) suggested that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, may allow stratification of prostate cancer into distinct survival categories. Ammirante et al. (2010) found that prostate cancer progression is associated with inflammatory infiltration and activation of IKK-alpha (600664), which stimulates metastasis by an NF-kappa-B (see 164011)-independent cell-autonomous mechanism (Luo et al., 2007). Ammirante et al. (2010) showed that androgen ablation causes infiltration of regressing androgen-dependent tumors with leukocytes, including B cells, in which IKK-beta (603258) activation results in production of cytokines that activate IKK-alpha and STAT3 (102582) and prostate cancer cells to enhance hormone-free survival. Goldstein et al. (2010) showed that basal cells from primary benign human prostate tissue could initiate prostate cancer in immunodeficient mice. The cooperative effects of AKT (164730), ERG, and AR in basal cells recapitulated the histologic and molecular features of human prostate cancer, with loss of basal cells and expansion of luminal cells expressing PSA and alpha-methylacyl-CoA racemase (AMACR; 604489). Goldstein et al. (2010) concluded that the histologic characterization of cancers does not necessarily correlate with the cellular origins of the disease. ANIMAL MODEL Prostate cancer may become resistant to treatment with androgen deprivation therapy (ADT). Niu et al. (2008) demonstrated that the prostate AR (313700) may function as both a suppressor and a proliferator of prostate cancer metastasis, depending on its tissue location. Coculture of human stromal prostate WPMY1 cells with human AR-null epithelial prostate cancer PC3 cells showed that knockdown of AR in WPMY1 cells or restoration of AR in PC3 cells suppressed prostate cancer metastasis. Furthermore, in bone lesion assays and in vivo mouse models of prostate cancer, restoration of the AR in PC3 epithelial cells resulted in decreased tumor invasion. Knockdown of the AR in epithelial ADT-resistant prostate cancer cells resulted in increased cell invasion in vitro and in vivo. Transgenic mice lacking the prostate epithelial AR showed increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells, which coincided with larger and more invasive metastatic tumors and earlier death compared to wildtype mice. An evaluation of human prostate tumors showed a significant difference in AR expression between primary (91.75%) and metastatic (67.86%) prostate tumors. Together, these results indicated that AR functions in epithelial cells as a tumor suppressor of prostate cancer metastasis, whereas AR acts in stromal cells as a stimulator of prostate cancer progression. ► ▼ PROSTATE CANCER, HEREDITARY, 6* 609558 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. MAPPING Xu et al. (2005) performed genomewide linkage analysis in 269 prostate cancer families with at least 5 affected members and found significant linkage at chromosome 22q12 (lod score, 3.57). Camp et al. (2006) noted that at least 8 other studies had pointed to chromosome 22q12.3 as a site of particular significance in prostate cancer, with lod scores ranging from 1.50 to 3.57. They performed fine mapping and localization of the region using a pedigree-specific recombinant mapping approach in 14 informative, high-risk Utah pedigrees. These 14 pedigrees were chosen because they were either 'linked' or 'haplotype-sharing' pedigrees or both. 'Linked' pedigrees were those with significant pedigree-specific linkage evidence pointing to the 22q12.3 region, regardless of the number of prostate cancer cases sharing the segregating haplotype. 'Haplotype-sharing' pedigrees were those with at least 5 prostate cancer cases sharing a segregating haplotype in the 22q12.3 region, regardless of the linkage evidence. Using this approach, Camp et al. (2006) identified a segment at 22q12.3 between markers D22S1265 and D22S277 as the region most likely to contain the 22q prostate cancer predisposition gene. To further refine the linkage of prostate cancer to chromosome 22q12.3, Camp et al. (2007) added 40 new pedigrees with prostate cancer to the 14 Utah kindreds from their previous study. When all 54 pedigrees were considered, the consensus region was narrowed to a 2.2-Mb region flanked by D22S281 and D22S683, which included 11 genes. Johanneson et al. (2008) performed fine mapping using haplotype and recombination data from 42 high-risk families and found that no clear consensus interval was present when all families were used. However, in a subset of 14 families with 5 or more affected men per family, they identified a 2.53-Mb shared consensus segment overlapping the previously published interval; combining their results with earlier data reduced the critical region at chromosome 22q12.3 to approximately 1.36 Mb. ► ▼ BREAST CANCER 114480 only shown in mice INHERITANCE: Autosomal dominant NEOPLASIA: Breast carcinoma MISCELLANEOUS: Genetic heterogeneity, see also BRCATA (600048), BRCA3 (605365), AR (313700) MOLECULAR BASIS: Caused by mutations in the breast cancer type 1 gene (BRCA1, 113705.0001); Caused by mutations in the breast cancer type 2 gene (BRCA2, 600185.0001); Caused by mutations in the solute carrier family 22, member 1-like gene (SLC22A1L, 602631.0001); Caused by mutations in the tumor protein p53 gene (TP53, 191170.0023); Caused by mutations in the BRCA1-associated C-terminal helicase 1 gene (BRIP1, 605882.0001); Caused by mutations in the homolog of the S. cerevisiae RAD51A gene (RAD51A, 179617.0001; Susceptibility conferred by mutations in the homolog of the S. pombe checkpoint kinase 2 gene (CHEK2, 604373.0007) A number sign (#) is used with this entry because of evidence that mutation at more than one locus can be involved in different families or even in the same case. These loci include BRCA1 (113705) on 17q, BRCA2 (600185) on 13q12, BRCATA (600048) on 11q, BRCA3 (605365) on 13q21, BWSCR1A (602631) on 11p15.5, the TP53 gene (191170) on 17p, and the RB1CC1 gene (606837) on 8q11. Mutations in the androgen receptor gene (AR; 313700) on the X chromosome have been found in cases of male breast cancer (313700.0016). Mutation in the RAD51 gene (179617) was found in patients with familial breast cancer (179617.0001). Breast cancer susceptibility alleles have been reported in the CHEK2 gene (see 604373.0001 and 604373.0012) and in the BARD1 gene (see 601593.0001). Germline and somatic mutations in the CDH1 gene (192090) have been found in lobular breast cancer (see 192090.0004 and 192090.0021). Furthermore, the PPM1D gene (605100) on 17q is commonly amplified in breast cancer and appears to lead to cell transformation by abrogating p53 (191170) tumor suppressor activity (Bulavin et al., 2002). Somatic mutations in the PIK3CA gene (171834) and the AKT1 gene (164730) have also been identified in breast cancer. An allele of the CASP8 gene (601763.0003) has been associated with reduced risk of breast cancer. An allele of the TGFB1 gene (190180.0007) has been associated with an increased risk of invasive breast cancer. An allele of the NQO1 gene (125860.0001) has been associated with breast cancer prognosis, including survival after chemotherapy and after metastasis. Variation in the HMMR gene (600936) has also been shown to modify susceptibility. Mutations in genes responsible for various forms of Fanconi anemia (see, e.g., 227650) have been identified as susceptibility factors for breast cancer. These include BRCA2, PALB2 (610355), BRIP1 (605882), and RAD51C (602774). Breast cancer is a feature of several cancer syndromes, including Li-Fraumeni syndrome (151623) due to germline mutations in p53; Cowden syndrome (158350) due to mutations in the PTEN gene (601728); and Peutz-Jeghers syndrome (175200) due to mutations in the STK11 gene (602216). There also appears to be an increased risk of breast and ovarian cancer in ataxia-telangiectasia (208900), and there is some evidence that heterozygotes for some mutations in the ataxia-telangiectasia mutated gene (ATM; e.g., 607585.0032) have an increased risk of breast cancer. Some genomic regions have been found to be amplified in breast cancer, including 8q24, 20q13, 11q12, and 8p12-p11 (Yang et al., 2006). The NCOA3 (601937) and ZNF217 (602967) genes, located on 20q, undergo amplification in breast cancer; when overexpressed, these genes confer cellular phenotypes consistent with a role in tumor formation (Anzick et al., 1997; Collins et al., 1998). DESCRIPTION Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. CLINICAL FEATURES Cady (1970) described a family in which 3 sisters had bilateral breast cancer. Together with reports in the literature, this suggested to him the existence of families with a particular tendency to early-onset, bilateral breast cancer. The genetic basis might, of course, be multifactorial. Anderson (1974) concluded that the sisters of women with breast cancer whose mothers also had breast cancer have a risk 47 to 51 times that in control women; a revised estimate was 39 times (Anderson, 1976). The disease in these women usually developed before menopause, was often bilateral, and seemed to be associated with ovarian function. About 30% of daughters with early-onset, bilateral breast cancer inherited the susceptibility. The risk of breast cancer to women with affected relatives is higher when the diagnosis is made at an early age and when the disease is bilateral. Ottman et al. (1983) provided tables that give the cumulative risk of breast cancer to mothers and sisters at various ages. The highest risk group is sisters of premenstrual probands with bilateral disease. Among the sisters of women with breast cancer, Anderson and Badzioch (1985) found the highest lifetime risks when the proband had bilateral disease, an affected mother (25 +/- 7.2%), or an affected sister (28 +/- 11%). The risks were reduced to 18 +/- 3.3% and 14 +/- 2.6%, respectively, with unilateral disease. An early example of familial breast cancer was provided by Broca (1866). According to the pedigree drawn by Lynch (1976), 10 women in 4 generations of the family of Broca's wife died of breast cancer. Eisinger et al. (1998) called attention to an even earlier report of hereditary breast cancer by Le Dran (1757), who related the experience of a colleague in Avignon who had diagnosed a 19-year-old nun with cancer of the right breast. The patient refused a mastectomy not only because of the pain of surgery, but also because of a belief that the operation would be futile. Her grandmother and a grandmaternal uncle died with breast cancer, and she was convinced that this malady was hereditary and that 'her blood was corrupted by a cancerous ferment natural to her family.' Two families with an extraordinary incidence of male breast cancer and father-to-son transmission of same was reported by Everson et al. (1976). They found a suggestion of elevated urinary estrogen in 3 of the affected males. Teasdale et al. (1976) described breast cancer in 2 brothers and in a daughter of 1 brother. Kozak et al. (1986) reported breast cancer in 2 related males, an uncle and nephew. In this family and in several reported families with male breast cancer, Kozak et al. (1986) found women in the same family with breast cancer. Soft tissue sarcomas are associated with breast cancer in Li-Fraumeni syndrome. Mulvihill (1982) used the term cancer family syndrome of Lynch (120435) for the association of colon and endometrial carcinoma and other neoplasms including breast cancer. Seltzer et al. (1990) concluded that dermatoglyphics can help in the identification of women either with or at risk for breast cancer. They found that the presence of 6 or more whorls is associated in a statistically significant manner with breast cancer. Marger et al. (1975) presented the cases of 2 brothers with breast cancer and reviewed the courses of 28 other previously unreported male patients. In one of the brothers, breast cancer was preceded by prostate cancer and estrogen administration, raising the possibility that the breast cancer was a metastatic deposit. The possibility of prostatic metastases was raised in 2 other patients. Demeter et al. (1990) reported breast cancer in a 64-year-old man who had had bilateral gynecomastia since childhood. His maternal grandfather had been found to have adenocarcinoma of the breast at the age of 65. His maternal grandmother had radical mastectomy for breast cancer at the age of 66 and 2 years later underwent radiation therapy for rib metastases. The proband's sister developed breast cancer at the age of 31 years and despite aggressive therapy died 1 year later with extensive metastases. Hauser et al. (1992) reported a family in which 2 females and 2 males in 2 generations had breast cancer. Two females in the family had prophylactic bilateral mastectomy at a young age. One male developed a left breast mass and axillary node at age 59 and died of metastatic disease at age 62. His paternal uncle presented at age 57 years with bleeding from his right breast. Biopsy suggested Paget disease of the breast and he underwent mastectomy. He subsequently died at age 75 years of prostatic carcinoma. He had a daughter who developed breast cancer at age 27 years and died at age 30 with disseminated disease, and a son who developed infiltrating grade 4 adenocarcinoma of the breast at age 54. OTHER FEATURES Chang et al. (1987) showed that the noncancerous skin fibroblasts of members of a family with Li-Fraumeni syndrome (which show resistance to the killing effect of ionizing radiation) have a 3- to 8-fold elevation in expression of the MYC oncogene (190080) and an apparent activation of the RAF1 gene (164760). Normal fetal and adult skin fibroblasts show distinctive migratory behavior when plated on 3-dimensional collagen gels. Haggie et al. (1987) found that skin fibroblasts from 13 of 15 patients with hereditary breast cancer showed fetal-like behavior compared with only 1 of 12 age-matched healthy controls. In addition, 10 of 15 first-degree relatives of patients with hereditary breast cancer showed a fetal-like fibroblast phenotype, compared with none of 7 surgical controls. Using x-ray diffraction studies with synchrotron radiation, James et al. (1999) found that hair from breast cancer patients had a different intermolecular structure than hair from healthy subjects. All 23 patients with breast cancer, including 8 without BRCA1 mutations, had altered hair structure. Of 5 women without breast cancer but carrying BRCA1 mutations, 3 had fully different structure and 2 had partial changes in hair structure. The authors proposed hair analysis to screen for breast cancer, but suggested additional study of the sensitivity and specificity of the test. Briki et al. (1999) repeated the studies of James et al. (1999), using scalp hair from 10 supposedly healthy people, 7 females and 3 males, and 10 breast cancer patients, all female. They irradiated a bundle of hair in a glass capillary with a 0.5-mm monochromatic x-ray beam. The diffraction patterns from healthy subjects displayed an intense ring at 4.48 +/- 0.05 nm. Eight of the 10 breast cancer patients had the same ring. These results were exactly the opposite of those observed by James et al. (1999). However, the study by Briki et al. (1999) used scalp hair rather than pubic hair. Breast cancer metastasis occurs in a distinct pattern involving the regional lymph nodes, bone marrow, lung, and liver, but rarely other organs. By real-time quantitative PCR, immunohistochemistry, and flow cytometric analysis, Muller et al. (2001) found that CXCR4 is highly expressed in primary and metastatic human breast cancer cells but is undetectable in normal mammary tissue, whereas CCR7 (600242) is highly expressed in normal tissue and is upregulated in breast cancer cells. Quantitative PCR analysis also detected peak expression levels of the CXCR4 ligand, CXCL12 (SDF1; 600835) in lymph nodes, lung, liver, and bone marrow, while the CCR7 ligand, CCL21 (602737), is most abundant in lymph nodes, the organs to which primary breast cancer cells preferentially migrate. Analysis of malignant melanomas determined that in addition to CXCR4 and CCR7, these tumors also had high levels of CCR10 (600240); its primary ligand is CCL27 (604833), a skin-specific chemokine involved in the homing of memory T cells into the skin. Flow cytometric analysis and confocal laser microscopy demonstrated that either CXCL12 or CCL21 induces high levels of F-actin polymerization and pseudopod formation in breast cancer cells. These chemokines, as well as lung and liver extracts, also induce directional migration of breast cancer cells in vitro, which can be blocked by antibodies to CXCR4 or CCL21. Histologic and quantitative PCR analyses showed that metastasis of intravenously or orthotopically injected breast cancer cells could be significantly decreased in SCID mice by treatment with anti-CXCR4 antibodies. Muller et al. (2001) proposed that the nonrandom expression of chemokine receptors in breast cancer and malignant melanoma, and probably in other tumor types, indicates that small molecule antagonists of chemokine receptors (e.g., Hendrix et al. (2000)) may be useful to interfere with tumor progression and metastasis in tumor patients. Liotta (2001) reviewed the theories explaining the bias of metastases toward certain organs and addressed questions raised by the work of Muller et al. (2001). Certain breast tumors are characterized by a high prediction uncertainty ('low-confidence') based on ESR1 (133430) expression status. Kun et al. (2003) analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ESR-subtype discrimination. Patients with 'low-confidence' ESR-positive tumors exhibited a significantly worse overall survival (p = 0.03) and shorter time to distant metastasis (p = 0.004) compared with their 'high-confidence' ESR-positive counterparts, indicating that the 'high' and 'low-confidence' binary distinction is clinically meaningful. Elevated expression of ERBB2 (164870) was significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ESR1, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2-positive samples are not known to be estrogen responsive. Kun et al. (2003) proposed that a significant portion of the effect of ERBB2 on ESR-positive breast tumors may involve ESR-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype. Kristiansen et al. (2002) reported an association between skewed X inactivation and breast cancer in young patients. Kristiansen et al. (2005) described the results of X inactivation analysis of 272 patients with familial breast cancer, 35 with BRCA1/BRCA2 germline mutations, and 292 with sporadic breast cancer. X inactivation pattern was determined by PCR analysis of the highly polymorphic CAG repeat in the androgen receptor gene (AR; 213700). Young patients with familial breast cancer had a significantly higher frequency of skewed X inactivation, defined as 90% or more of cells preferentially expressing one X chromosome. There was also a strong tendency for middle-aged patients with sporadic breast cancer to be more skewed than middle-aged controls. No association was found, however, between skewed X inactivation and breast cancer for BRCA1/BRCA2 patients. Kristiansen et al. (2005) interpreted the results as indicating that skewed X inactivation may be a risk factor for the development of breast cancer in both sporadic and familial breast cancer and may indicate an effect of X-linked genes. The acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. Podsypanina et al. (2008) reported that untransformed mouse mammary cells that have been engineered to express the inducible oncogenic transgenes Myc (190080) and Kras bearing the gly12 to asp mutation (190070.0005), or polyoma middle T, and introduced into the systemic circulation of a mouse can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogenic induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors. Hurtado et al. (2008) showed that estrogen-estrogen receptor (ER; see 133430) and tamoxifen-ER complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. Hurtado et al. (2008) implicated the paired box-2 gene product (PAX2; 167409) in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anticancer drug tamoxifen. Hurtado et al. (2008) showed that PAX2 and the ER coactivator AIB1/SRC3 (601937) compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these 2 breast cancer subtypes and suggests that aggressive ERBB2-positive tumors can originate from ER-positive luminal tumors by circumventing this repressive mechanism. Hurtado et al. (2008) concluded that their data provided mechanistic insight into the molecular basis of endocrine resistance in breast cancer. Using microarray analysis, Miller et al. (2008) found increased expression of MIRN221 (300568) and MIRN222 (300569) in human breast cancer cells that were resistant to tamoxifen compared to parental cancer cells that were sensitive to tamoxifen. MIRNR221 and MIRNR222 expression was also increased about 2-fold in ERBB2-positive breast cancer cells that are known to be resistant to tamoxifen. Increased expression of the microRNAs was associated with decreased expression of the cell cycle inhibitor CDKN1B (600778). Ectopic expression of MIRN221 or MIRN222 rendered sensitive breast cancer cells resistant, and, conversely, overexpression of CDKN1B enhanced cell death when exposed to tamoxifen. Zhao et al. (2008) found increased expression of MIRN221 and MIRN222 in ESR1-negative breast cancer cells and tumors. MIRN221 and MIRN222 directly interacted with the 3-prime untranslated region of ESR1 mRNA, resulting in decreased ESR1 protein expression and tamoxifen resistance. Knockdown of MIRN221 and MIRN222 restored ESR1 expression and tamoxifen sensitivity. Li et al. (2010) found a significant association between amplification of a region on chromosome 8q22 and de novo chemoresistance to anthracyclines and metastatic recurrence in human breast cancer. Within this region, overexpression of both the YWHAZ (601288) and LAPTM4B (613296) genes was found to correlate with the observations. Knockdown of either of these genes using siRNA resulting in sensitivity of tumor cells to anthracyclines. Extensive in vitro studies confirmed the effect. Further studies indicated that LAPTM4B resulted in sequestration of anthracycline and delayed entry into the nucleus, whereas YWHAZ likely protected cells from apoptosis. The findings were specific to anthracyclines. INHERITANCE Petrakis (1977) listed the evidence for a genetic role in breast cancer as follows: 1) family history of breast cancer, especially bilateral breast cancer; 2) marked differences in rates between certain racial groups (lower in Orientals); 3) lack of major change in incidence over many years despite dramatic decline in other cancers; 4) concordance in monozygotic twins; and 5) concordance of laterality in closely related persons. Lynch et al. (1984) found evidence consistent with a hereditary breast cancer syndrome in 5% of 225 consecutively ascertained patients with verified breast cancer. From a maximum-likelihood mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and the lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. They concluded that inherited susceptibility affected only 4% of the families in the sample; multiple cases of this relatively common disease occurred in other families by chance. They pictured an extended pedigree with 14 cases of breast cancer, 3 of them in men. The Danish twin registry (Holm et al., 1980) had 5 out of 45 MZ twins and 4 out of 77 DZ twins concordant for breast cancer; heritability was calculated at 0.3-0.4. From complex segregation analysis of 200 Danish breast cancer pedigrees, Williams and Anderson (1984) concluded that the distribution of cases was compatible with transmission of an autosomal dominant gene. Newman et al. (1988) used complex segregation analysis to investigate patterns of breast cancer occurrence in 1,579 nuclear families. They concluded that an autosomal dominant model with a highly penetrant susceptibility allele fully explains disease clustering. Iselius et al. (1992) reanalyzed the Danish breast cancer data collected by Jacobsen (1946), using morbid risks that incorporate mortality due to breast cancer. They interpreted the results to favor a dominant gene for familial breast cancer. No evidence of heterogeneity was found. Cases with bilateral breast cancer and males with breast cancer all belonged to families favoring a major gene. Of the cancer sites frequently reported to be associated with familial breast cancer, only ovarian cancer was significant in this study. Houlston et al. (1992) showed that the risk of breast cancer increased progressively in inverse relationship to the age of the index patient. First-degree relatives of patients with bilateral breast cancer had a 6.43-fold increase in risk. Houlston et al. (1992) estimated that the genetic contribution to overall lifetime liability to breast cancer in relatives declined with increasing age of onset of breast cancer in the index case from 37% at 20 years to 8% by 45 years. In Iceland, Tulinius et al. (1992) likewise found that early onset and bilaterality of breast cancer increased the risk to relatives. In an analysis of a prospective cohort study, Sellers et al. (1992) found that the increase in the risk of breast cancer associated with a high waist-to-hip ratio (the circumference of the waist divided by that of the hips), low parity, or greater age at first pregnancy was more pronounced among women with a family history of breast cancer. They concluded that there are etiologic differences between familial breast cancer and the sporadic form. Tumors are believed to emerge only when immune surveillance fails. To ascertain whether the failure to inherit putative protective alleles of HLA class II genes is linked to the development of breast cancer, Chaudhuri et al. (2000) performed molecular typing of HLA alleles in 176 Caucasian women diagnosed with early-onset breast cancer and in 215 ethnically matched controls. HLA DQB03032 was identified in 7% of controls but in no patients with early-onset breast cancer (P = 0.0001). HLA DRB111 alleles were also significantly overrepresented (P less than 0.0001) in controls (16.3%) as compared with patients with early-onset breast cancer (3.5%). Ritchie et al. (2001) introduced multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, thereby improving the identification of polymorphism combinations associated with disease risk. Using simulated case-control data, they demonstrated that MDR has reasonable power to identify interactions among 2 or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control dataset, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among 4 polymorphisms from 3 different estrogen metabolism genes: COMT (116790), CYP1A1 (108330), and CYP1B1 (601771). To study possible genetic components in breast cancer in addition to BRCA1 and BRCA2, Cui et al. (2001) conducted single-locus and 2-locus segregation analyses, with and without a polygenic background, using 3-generation families ascertained through 858 Australian women with breast cancer diagnosed at age less than 40 years. Extensive testing for deleterious mutations in BRCA1 and BRCA2 had identified 34 carriers. Their analysis suggested that, after other possible unmeasured familial factors are considered and the known BRCA1 and BRCA2 mutation carriers are excluded, there is a residual dominantly inherited risk of female breast cancer. The study also suggested that there is a substantial recessively inherited risk of early-onset breast cancer. Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Menopausal status, weight, and parity account for 20 to 30% of the age-adjusted variation in the percentage of dense tissue. Boyd et al. (2002) undertook 2 studies of twins to determine the proportion of the residual variation in percentage of density measured by mammography that can be explained by the unmeasured additive genetic factors (heritability). A total of 353 pairs of monozygotic twins and 246 pairs of dizygotic twins were recruited from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins were recruited in Canada and the United States. After adjustment for age and measured covariates, the correlation coefficient for the percentage of dense tissue was 0.61 for monozygotic pairs in Australia, 0.67 for monozygotic pairs in America, 0.25 for dizygotic pairs in Australia, and 0.27 for dizygotic pairs in North America. According to the classic twin model, heritability (the proportion of variance attributable to additive genetic factors) accounted for 60% of the variation in density in Australian twins, 67% in North American twins, and 63% in all twins studied. The authors concluded that mammographic density may be associated with an increased risk of breast cancer. Hamilton and Mack (2003) used a novel design of a twin study by investigating twin pairs concordant or discordant for breast cancer. On the basis of the very high relative and cumulative risk to a woman who is genomically identical to a woman with cancer, disease in monozygotic twins who were both affected was considered largely to represent hereditary cancer, whereas disease in only 1 twin of a pair was believed to represent sporadic, or less heritable, disease. Cases among disease-discordant dizygotic pairs represent the same mixture of heritable and sporadic cases as those seen in ordinary case-control studies. The analysis reported by Hamilton and Mack (2003) was based on a previously described population (Peto and Mack, 2000) and included all twins in affected pairs who completed a risk factor questionnaire. To determine whether risk factors differed according to genetic susceptibility, they stratified pairs on the basis of zygosity, concordance or discordance of disease, the presence of bilateral or unilateral disease, and the presence or absence of a family history of breast cancer. Hamilton and Mack (2003) found that within disease-discordant monozygotic twins, the twin with an earlier onset of puberty did not have an increased risk of breast cancer. Within disease-concordant monozygotic pairs, the twin with earlier puberty was much more likely to receive the diagnosis first. In contrast, a later first pregnancy, lower parity, and later menopause within the pair was associated with an increased risk of breast cancer when 1 twin was affected but did not predict an earlier diagnosis when both were affected. The absence of linkage to hormonal milestones later in life suggested that most cases of hereditary breast cancer are not related to cumulative hormone exposure and that they may instead result from an unusual sensitivity to pubertal hormones. Associations between breast cancer and early menarche and those with reproductive milestones in adulthood may reflect different genotypes. Hamilton and Mack (2003) did not genotype the twins for mutations in BRCA1 or BRCA2. They suspected that few of the monozygotic concordant twins carried mutations in these genes. Contrariwise they suspected that the twins had potent combinations of common genetic variants that, individually, would be less influential. Thus, genotyping might reveal polymorphisms important in many other women. DIAGNOSIS Van't Veer et al. (2002) used DNA microarray analysis on primary breast tumors of 117 young patients and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases in patients without tumor cells in local lymph nodes at diagnosis. In addition, they established a signature that identified tumors of BRCA1 carriers. Van't Veer et al. (2002) concluded that their gene expression profile (which consists of 70 genes) could outperform all currently used clinical parameters in predicting disease outcome, and provide a strategy to select patients who would benefit from adjuvant therapy. Pharoah et al. (2002) examined the polygenic basis of susceptibility to breast cancer. Availability of the human genome sequence makes possible the identification of individuals as susceptible to breast cancer by their genotype profile. They examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data were compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. The results suggested that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases. Although germline mutations in the BRCA1 and BRCA2 genes account for most cases of familial breast and ovarian cancer, a large proportion of cases segregating familial breast cancer alone (i.e., without ovarian cancer) are not caused by mutations in either of these genes. Hedenfalk et al. (2003) noted that identification of additional breast cancer predisposition genes had been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/BRCA2 families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Hedenfalk et al. (2003) showed that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrated that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis. CLINICAL MANAGEMENT Hartmann et al. (1999) identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Their analyses suggested a reduction in the incidence of breast cancer of at least 90%. MAPPING - Associations Pending Confirmation Goldstein et al. (1989) found a suggestion of linkage to acid phosphatase (ACP1; 171500) on chromosome 2p25 (maximum lod score = 1.01 at theta = 0.001). Narod and Amos (1990) analyzed the effects of phenocopies and genetic heterogeneity on the demonstration of linkage between a putative cancer susceptibility gene and polymorphic DNA markers. De Jong et al. (2003) genotyped 956 breast cancer patients and 1,271 family-based controls at SNPs in TNFA (191160) and TNFB (153440), as well as at 24 microsatellite markers over the HLA region on chromosome 6p. There was a significant difference in mean haplotype sharing between patients and controls for 4 consecutive markers (D6S2671, TNFA, D6S2672, and MICA, 600169), the highest being at D6S2671 (p = 0.017). A single haplotype was more frequent and longer in moderate-risk patients than in controls. Individuals homozygous for haplotype 110-184 (D6S2672-MICA) were observed in 9.0% of moderate-risk patients and 1.5% of controls (odds ratio = 7.14), while heterozygotes were at a lower risk (odds ratio = 1.41), suggesting a recessive effect. No association was observed between the 2 SNPs in TNFA and TNFB and breast cancer risk. The authors concluded that there may be a potential role of the HLA class III subregion in susceptibility to breast cancer in patients at moderate familial risk. Easton et al. (2007) conducted a 2-stage genomewide association study of 4,398 familial breast cancer cases, followed by a third stage in which 30 SNPs were tested for confirmation in 22,848 cases from 22 studies. The study identified 5 novel independent loci associated with breast cancer, each at a significance level of p less than 10(-7). Four plausible genes were involved with the identified SNPs: dbSNP rs2981582 in FGFR2 (176943) on chromosome 10q26; dbSNP rs889312 in MAP3K1 (600982) on chromosome 5; dbSNP rs3817198 in LSP1 (153432) on chromosome 11p15.5; and dbSNP rs12443621, dbSNP rs8051542, and dbSNP rs3803662 in the TNRC9 (TOX3; 611416)/LOC643714 gene on chromosome 16q. Another SNP, dbSNP rs13281615, on chromosome 8q was not located in any known gene. Easton et al. (2007) found that all of these susceptibility alleles are very common in the U.K. population and thus likely show a small increased disease risk individually. However, in combination, the SNPs may become clinically significant. In a genomewide association study of over 2,100 Icelandic patients with breast cancer, Stacey et al. (2007) identified 2 SNPs, dbSNP rs13387042 and dbSNP rs3803662, located on chromosomes 2q35 and 16q12, respectively, that were significantly associated with disease. The findings were replicated in 5 sample sets totaling 2,350 European and European American breast cancer patients. The overall risk was confined to estrogen receptor (see ESR1, 133430)-positive tumors. The A allele of dbSNP rs13387042 had an odds ratio of 1.44 (combined p = 1.3 x 10(-13)), and the T allele of dbSNP rs3803663 had an odds ratio of 1.64 (combined p = 5.9 x 10(-19)) Hunter et al. (2007) identified a SNP (dbSNP rs1219648) in intron 2 of the FGFR2 gene that was significantly (p = 1.0 x 10(-10)) associated with sporadic postmenopausal breast cancer in a 2-stage genomewide association study of 1,145 and 1,776 affected individuals of European ancestry, respectively. The pooled odds ratios were 1.20 for heterozygotes and 1.64 for homozygotes. Among 5,028 patients with breast cancer and 32,090 controls of European ancestry, Stacey et al. (2008) found that 2 SNPs on chromosome 5p12, dbSNP rs4415084 and dbSNP rs10941679, were associated with increased risk for estrogen receptor-positive breast cancer. The T allele of dbSNP rs4415084 yielded an OR of 1.16 (P = 6.4 x 10(-10) after Bonferroni correction), and an OR of 1.14 (P = 7.5 x 10(-5)) in the replication sample. The G allele of dbSNP rs10941679 yielded an OR of 1.19 (P = 2.9 x 10(-11)). The results were not significant for estrogen receptor-negative cases, suggesting that estrogen receptor-positive and estrogen receptor-negative tumors have different genetic components to their risks. Antoniou et al. (2009) evaluated the association of SNPs dbSNP rs3817198 at LSP1, dbSNP rs13387042 at 2q35, and dbSNP rs13281615 at 8q24 with breast cancer risk in 9,442 BRCA1 (113705) and 5,665 BRCA2 (600185) mutation carriers from 33 study centers. The minor allele (C) of dbSNP rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers (P trend = 2.8 x 10(-4)). The best fit for the association of SNP dbSNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1, P = 0.0047; BRCA2, P = 0.0079). SNP dbSNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appeared to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations varied by mutation type depending on whether the mutated protein was predicted to be stable. In a SNP-based genomewide scan of 41 Spanish families with non-BRCA1/BRCA2 breast cancer, with an average of 4 female breast cancer cases per family and with no blood relatives affected with ovarian or male breast cancer, Rosa-Rosa et al. (2009) found linkage to 3 regions of interest on chromosomes 3q25 (HLOD score of 3.01), 6q24 (HLOD score of 2.26), and 21q22 (HLOD score of 3.55). A subset of 13 families with bilateral breast cancer presented an HLOD of 3.13 in the 3q25 region. By a genomewide linkage analysis of 55 high-risk Dutch breast cancer families without mutations in the BRCA1 or BRCA2 genes and replication studies in an additional 30 families, Oldenburg et al. (2008) found linkage to a region on chromosome 9q21-q22 (nonparametric multipoint lod score of 3.96 at D9S167). However, a parametric HLOD of 0.56 was also found, indicating that most families did not show linkage to this region. No pathogenic changes were found in 5 genes within the candidate region. Zheng et al. (2009) performed a genomewide association study of 1,505 Chinese women with breast cancer and 1,522 controls, followed by replication studies in a second set of 1,554 cases and 1,576 controls and a third set of 3,472 cases and 900 controls. SNP dbSNP rs2046210 at chromosome 6q25.1, located upstream of the ESR1 gene, showed strong and consistent association with breast cancer across all 3 sets. Adjusted odds ratios were 1.36 and 1.59, respectively, for genotypes A/G and A/A, compared to G/G (p value for trend was 2.0 x 10(-15)) in the pooled analysis. These results implicated chromosome 6q25.1 as a susceptibility locus for breast cancer. Thomas et al. (2009) conducted a 3-stage genomewide association study of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility initiative. In stage 1, 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls were genotyped. In stage 2, 24,909 top SNPs in 4,547 cases and 4,434 controls were analyzed. In stage 3, 21 loci in 4,078 cases and 5,223 controls were investigated. Two new loci achieved genomewide significance. A pericentromeric SNP on chromosome 1p11.2 (dbSNP rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen receptor-positive tumors. A second SNP on chromosome 14q24.1 (dbSNP rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1 (602948), a gene in the homologous recombination DNA repair pathway. Thomas et al. (2009) also confirmed associations with loci on chromosome 2q35, 5p12, 5q11.2, 8q24, 10q26, and 16q12.1. Ahmed et al. (2009) tested over 800 promising associations detected by Easton et al. (2007) in a further 2 stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. Ahmed et al. (2009) found strong evidence for additional susceptibility loci on 3p (dbSNP rs4973768; per-allele odds ratio = 1.11, 95% confidence interval = 1.08-1.13; P = 4.1 x 10(-23)) and 17q (dbSNP rs6504950; per allele odds ratio = 0.95, 95% confidence interval = 0.92-0.97, P = 1.4 x 10(-8)). Ahmed et al. (2009) postulated that the potential causative genes include SLC4A7 (603353) and NEK10 on 3p and COX11 (603648) on 17q. - Exclusion Mapping King et al. (1980) presented evidence suggestive of linkage of breast cancer to the glutamate-pyruvate transaminase gene (GPT; 138200) on chromosome 8q24. Analysis of 6 families with the disorder yielded a lod score of 1.84; all 11 families yielded a score of 1.43. However, in Mormon breast cancer pedigrees McLellan et al. (1984) excluded linkage to GPT (cumulative lod score of -3.86). Goldstein et al. (1989) excluded linkage between breast cancer and the genes ABO, GC, GPT, MNS, and PGM1. In 12 high-risk families with breast cancer, Hall et al. (1990) excluded linkage to the HRAS gene (190020) on 11p (lod score of -19.9). By linkage studies, Bowcock et al. (1990) excluded the retinoblastoma gene (RB; 180200) on 13q14 and 13q in general as the site of the primary lesion in breast cancer. Abnormality there was sought because of observation of LOH of alleles on 13q in some ductal breast tumors and because 2 breast cancer lines had been found to have an alteration in the retinoblastoma gene. CYTOGENETICS In breast cancer tissue, Pathak and Goodacre (1986) found somatic reciprocal translocations involving 1q21 and chromosomes 3, 5, 10, 11. Chen et al. (1989) demonstrated loss of heterozygosity (LOH) in the region 1q23-q32. MOLECULAR GENETICS - Somatic Changes A previously reported loss of alleles at the HRAS locus, located at 11p14, in about 20% of breast cancer tumors was confirmed by Mackay et al. (1988). Comparing tumor and blood leukocyte DNA from a consecutive series of patients with primary breast cancer, Mackay et al. (1988) found that 61% of the tumors had allele loss demonstrated with a probe located at 17p13.3. Coles et al. (1990) mapped regions of LOH on chromosome 17 by comparing DNA of paired tumor and blood leukocyte samples. They confirmed a high frequency of LOH on 17p, where 2 distinct regions of LOH were identified in bands p13.3 and p13.1. The latter probably involves the structural gene TP53 (191170). The frequency of LOH was higher, however, at 17p13.3, and there was no correlation between allele loss at the 2 sites. Since LOH at 17p13.3 was associated with overexpression of p53 mRNA, Coles et al. (1990) suggested the existence of a gene some 20 megabases telomeric of TP53 that regulates its expression; see 113721. They concluded that lesions of this regulatory gene are involved in the majority of breast cancers. Devilee et al. (1991) reported LOH data. Davidoff et al. (1991) found that in 11 (22%) of 49 primary invasive human breast cancers, widespread overexpression of p53 was indicated by immunohistochemical staining. The p53 gene was directly sequenced in 7 of the tumors with elevated levels of protein, and in each case a mutation that altered the coding sequence for p53 was found in a highly conserved region of the gene. Whereas 4 of these tumors contained only a mutant p53 allele, the other 3 exhibited coding sequences from both a mutant and a wildtype allele. Six tumors that were deleted at or near the p53 locus but did not express high levels of the protein were sequenced and all retained a wildtype p53 allele. This was interpreted as indicating that overexpression of the p53 protein, not allelic loss, was associated with mutation of the p53 gene. The ARHGEF5 (600888) oncogene belongs to the DBL family of guanine nucleotide exchange factors (GEFs) for RHO GTPases. Debily et al. (2004) identified 5 novel ARHGEF5 alternative transcripts specifically expressed in breast tumors, which were predicted to generate modified or truncated proteins. Histologic features suggested that ARHGEF5 may activate RAC1 (602048), CDC42 (116952), or ARHG (179505) rather than ARHA (165390). The authors hypothesized that activation of the ARHGEF5 oncogene, possibly by variant isoforms, may play a role in proliferative breast disease. By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Sjoblom et al. (2006) determined the sequence of well-annotated human protein-coding genes in 2 common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of about 90 mutant genes, but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, Sjoblom et al. (2006) identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these were not known to be genetically altered in tumors and were predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. Sjoblom et al. (2006) concluded that their data defined the genetic landscape of 2 human cancer types, provided new targets for diagnostic and therapeutic intervention, and opened fertile avenues for basic research in tumor biology. Forrest and Cavet (2007), Getz et al. (2007), and Rubin and Green (2007) commented on the article by Sjoblom et al. (2006), citing statistical problems that, if addressed, would result in the identification of far fewer genes with significantly elevated mutation rates. Parmigiani et al. (2007) responded that the conclusions of the above authors were inaccurate because they were based on analyses that did not fully take into account the experimental design and other critical features of the Sjoblom et al. (2006) study. By array CGH, Yang et al. (2006) analyzed the copy number and expression level of genes in the 8p12-p11 amplicon in 22 human breast cancer specimens and 7 breast cancer cell lines. Of the 21 potential genes identified, PCR analysis and functional analysis indicated that 3 genes, LSM1 (607281), BAG4 (603884), and C8ORF4 (607702), are breast cancer oncogenes that could work in combination to influence a transformed phenotype in human mammary epithelial cells. To catalog the genetic changes that occur during tumorigenesis, Wood et al. (2007) isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, Wood et al. (2007) concluded that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene 'mountains' and a much larger number of gene 'hills' that are mutated at low frequency. Wood et al. (2007) described statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. The gene mountains were comprised of well-known cancer genes such as APC (611731), KRAS (190070), and TP53 (191170). Furthermore, Wood et al. (2007) observed that most tumors accumulated approximately 80 mutations, and that the majority of these were harmless. Fewer than 15 mutations are likely to be responsible for driving the initiation progression or maintenance of the tumor. Srivastava et al. (2008) found an alteration of the H2AFX (601772) gene copy number in 25 (37%) of 65 breast cancer tissues derived from patients with sporadic forms of the disorder. Gene deletion accounted for 19 (29%) of total cases and gene amplification for 6 (9%). Patients with estrogen and progesterone receptor (PGR; 607311)-positive tumors had more significantly altered copy numbers of H2AFX compared to those with ER/PR-negative tumors. None of the tissues contained H2AFX sequence alterations. Sotiriou and Pusztai (2009) reviewed gene expression signatures in breast cancer. Stephens et al. (2009) used a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromasomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by nonhomologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. Stephens et al. (2009) concluded that their study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development. Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. - Mutation in the BARD1 Gene on Chromosome 2q34-q35 In 7 of 126 (5.6%) index cases from Finnish families with breast and/or ovarian cancer, Karppinen et al. (2004) identified a cys557-to-ser substitution in the BARD1 gene (C557S; 601593.0001) at elevated frequency compared to healthy controls (5.6% vs 1.4%, p = 0.005). The highest prevalence of C557S was found among a subgroup of 94 patients with breast cancer whose family history did not include ovarian cancer (7.4% vs 1.4%, p = 0.001). Karppinen et al. (2004) concluded that C557S may be a commonly occurring and mainly breast cancer-predisposing allele. - Mutation in the CYP17A1 Gene on Chromosome 10q24.3 In 3 sisters with early-onset breast cancer (diagnosed at ages 34, 38, and 42 years, respectively) who did not have mutations in BRCA1 or BRCA2, Hopper et al. (2005) identified a germline R239X mutation in the CYP17A1 gene (609300.0006). A sister who was cancer-free at age 58 did not have the R239X mutation; the mutation was not found in 788 controls. Hopper et al. (2005) suggested that there may be rare mutations in steroid hormone metabolism genes associated with a high dominantly inherited breast cancer risk. Although Haiman et al. (2003) presented initial evidence that haplotypes in the CYP19A1 (107910) gene, which encodes the enzyme aromatase, were associated with increased risk for breast cancer, Haiman et al. (2007) did not find an association between haplotypes or SNPs in the CYP19A1 gene among 5,356 patients with invasive breast cancer and 7,129 controls composed primarily of white women of European descent. Haiman et al. (2007) found that common haplotypes spanning the coding and proximal 5-prime region of the CYP19A1 gene were significantly associated with a 10 to 20% increase in endogenous estrogen levels in postmenopausal women, but not with breast cancer. - Mutation in the PALB2 Gene on Chromosome 16p12 Mutations in the PALB2 gene (610355), which encodes a BRCA2-interacting protein, cause Fanconi anemia of complementation group N (FANCN; 610832). To investigate whether monoallelic PALB2 mutations confer susceptibility to breast cancer, Rahman et al. (2007) sequenced the PALB2 gene in individuals with breast cancer from familial breast cancer pedigrees in which mutations in BRCA1 or BRCA2 had not been found, and in 1,084 controls. They identified monoallelic truncating PALB2 mutations in 10 of 923 individuals with familial breast cancer and in none of the controls (P = 0.0004), and showed that such mutations confer a 2.3-fold higher risk of breast cancer. The results established PALB2 as a breast cancer susceptibility gene and further demonstrated the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition. - Association with the NQO2 Gene on Chromosome 6p25 In a hospital-based study of 893 Chinese breast cancer patients and 711 Chinese cancer-free controls, Yu et al. (2009) genotyped 11 polymorphisms of the NQO2 (160998) gene, which encodes NRH:quinone oxidoreductase-2 and has enzymatic activity on estrogen-derived quinones and is able to stabilize p53 (TP53; 191170). The authors identified significant association between the incidence of breast cancer and a 29-bp insertion/deletion polymorphism (29-bp I/D; p = 0.0027; OR, 0.76) and the dbSNP rs2071002 SNP (+237A-C; p = 0.0031; OR, 0.80), both of which are within the NQO2 promoter region. The findings were replicated in a second Chinese population of 403 familial/early-onset breast cancer patients and 1,039 controls. Decreased risk was associated with the D allele of 29 bp-I/D and the +237C allele of dbSNP rs2071002. The susceptibility variants within NQO2 were notably associated with breast carcinomas with wildtype p53. The 29-bp insertion allele introduced a transcriptional repressor Sp3 binding sites, and the authors demonstrated that the 237A allele of dbSNP rs2071002 abolished a transcriptional activator Sp1 binding site. Real-time PCR assay showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Yu et al. (2009) suggested that NQO2 is a susceptibility gene for breast carcinogenesis. PATHOGENESIS Tavazoie et al. (2008) searched for general regulators of cancer metastasis and found a set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential. They demonstrated that restoring the expression of these microRNAs in malignant cells suppressed lung and bone metastasis in human cancer cells in vivo. Of these microRNAs, miR126 (611767) restoration reduced overall tumor growth and proliferation, whereas miR335 (611768) inhibited metastatic cell invasion. miR335 regulates a set of genes whose collective expression in a large cohort of human tumors was associated with risk of distal metastasis. miR335 suppresses metastasis and migration through targeting of the progenitor cell transcription factor SOX4 (184430) and extracellular matrix component tenascin C (187380). Expression of miR126 and miR335 is lost in the majority of primary breast tumors from patients who relapse, and the loss of expression of either microRNA is associated with poor distal metastasis-free survival. Tavazoie et al. (2008) concluded that miR335 and miR126 are metastasis suppressor microRNAs in human breast cancer. Yang et al. (2009) found that overexpression of LCN2 (600181) in clones of human MFC-7 breast cancer cells induced expression of mesenchymal markers on these cells, including vimentin (VIM; 193060) and fibronectin (FN1; 135600), and downregulated the epithelial cell marker E-cadherin (CDH1; 192090), consistent with an epithelial to mesenchymal transition. Cell motility and invasiveness were also increased. The cancer cell clones with increased LCN2 expression also showed decreased ESR1 expression and increased SLUG (SNAI2; 602150) expression. Inhibition of LCN2 in aggressive breast cancer cells (MDA-MB-231) reduced migration and suppressed the mesenchymal phenotype. Studies in mice showed that breast cancer cells with high LCN2 expression resulted in increased local invasion and lymph node metastases compared to those with low LCN2 expression. In humans, increased urinary LCN2 levels correlated with invasive breast cancer. Overexpression of the hepatic growth factor (HGF; 142409) protein has been observed in breast cancer tissue, but not in normal breast epithelium, of some patients. Ma et al. (2009) identified a cis-acting DNA element located 750 bp upstream from the transcription start site of the human HGF promoter that acts as a transcriptional repressor. The promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which the authors termed 'deoxyadenosine tract element' (DATE). A scan of human breast cancer cells overexpressing HGF identified somatic truncating mutations within the DATE region of the HGF gene that modulated chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter. Truncating DATE variants with 25 or fewer deoxyadenosines were found in breast cancer tumors of 51% of African Americans and 15% of individuals of mixed European descent. Notably, breast cancer patients with the truncated DATE variant were substantially younger than those with a wildtype genotype. Stephens et al. (2009) used a pair-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. They found that there were more rearrangements in some breast cancers than had been previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromasomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicated that these have been mediated by nonhomologous end-joining DNA repair, although varying sequence patterns indicated that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. Stephens et al. (2009) concluded that their study provided a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development. Schramek et al. (2010) demonstrated that in vivo administration of medroxyprogesterone acetate (MPA), used in women for hormone replacement therapy and contraceptives, triggers massive induction of the key osteoclast differentiation factor RANKL (602642) in mammary gland epithelial cells. Genetic inactivation of the RANKL receptor RANK (603499) in mammary gland epithelial cells prevented MPA-induced epithelial proliferation, impaired expansion of CD49f(hi) stem cell-enriched population, and sensitized these cells to DNA damage-induced cell death. Deletion of RANK from the mammary epithelium resulted in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. Schramek et al. (2010) concluded that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer. Gonzalez-Suarez et al. (2010) showed that RANK and RANKL are expressed within normal, premalignant, and neoplastic mammary epithelium, and, using complementary gain-of-function and loss-of-function approaches, defined a direct contribution of this pathway in mammary tumorigenesis. Accelerated preneoplasias and increased mammary tumor formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacologic inhibition of RANKL attenuated mammary tumor development not only in hormone- and carcinogen-treated MMTV-RANK and wildtype mice, but also in the MMTV-neu transgenic spontaneous tumor model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in preneoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 (168461) levels. Gonzalez-Suarez et al. (2010) concluded that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. ANIMAL MODEL Parallels may exist with breast cancer in mice, which has long been studied from the viewpoint of genetic-viral etiology and pathogenesis. This story begins with Bittner's 'milk agent,' originally discovered by Bittner (1936); using reciprocal matings between high tumor and low tumor strains, the Jackson Laboratory staff showed in 1933 that the tumor incidence in F1 females was a function of the strain of the mother. Virologists demonstrated that the mouse mammary tumor virus (MMTV, also called MuMTV) is indeed transmitted through the milk and is an RNA virus seen in its mature form as the B particle. This was the first virus universally accepted in this country as a cancer-causing virus. Some mouse strains have been shown to carry a potent MMTV transmitted in milk and also in the egg and sperm (see review by Heston and Parks, 1977). Strains of mice purged of the MMTV by foster-nursing the young on a clean strain still show a low incidence of breast cancer developing at a late age. By introducing the cancer-enhancing gene A(vy), the incidence could be raised to 90%; however, the agent was not transmitted through the milk but by both eggs and sperm. In one strain developed by Muhlbock (1965), Bentvelzen (1972) demonstrated that the high incidence of mammary tumors was caused by an MMTV transmitted in milk, eggs, and sperm. Particles resembling B-type retroviruses have been identified in human milk (Moore et al., 1971); MMTV-related RNA has been found in some breast cancers (Axel et al., 1972) and a breast cancer cell line that releases retrovirus-like particles has been established (McGrath et al., 1974). Callahan et al. (1982) and Westley and May (1984) demonstrated sequences in normal human DNA that appear to be homologous to endogenous retroviral sequences. By transfection of NIH 3T3 mouse cells, Lane et al. (1981) demonstrated a transforming gene in a human mammary tumor cell line (MCF-7). See 164820 for information on the human homolog of the putative mammary tumor oncogene. HISTORY Familial breast cancer shares several features with hereditary tumors that satisfy the conditions predicted by the 2-hit hypothesis of Knudson (1971); tumors are frequently bilateral and multifocal. They tend to occur in premenopausal women, while the overall incidence of breast cancer shows a peak at postmenopausal age; and male relatives in high-risk families are more often affected than are males in the general population. Lundberg et al. (1987) tested their hypothesis that the pathogenesis of breast cancer in males and young females involves a chromosomal rearrangement that serves to unmask a recessive cancer gene. Lundberg et al. (1987) studied 10 cases of ductal breast cancer: 8 premenopausal females and 2 males. In 3 females and 1 male, somatic loss of constitutional heterozygosity was observed at loci on chromosome 13 in primary tumor tissue. In 2 cases, specific loss of heterozygosity at 3 distinct genetic loci along the length of chromosome 13 was observed. In a third case, concurrent loss of alleles at loci on chromosomes 2, 13, 14, and 20 was detected, whereas a fourth case showed loss of heterozygosity for chromosomes 5 and 13. In each instance, the data were consistent with loss of one of the homologous chromosomes by mitotic nondisjunction. The relative specificity of the events was suggested by the fact that analysis of loci on several other chromosomes showed retention of constitutional heterozygosity. On the other hand, analyses of other breast cancers, including comedocarcinoma, medullary carcinoma, and juvenile secretory carcinoma, showed no loss of alleles at loci on chromosome 13. Lundberg et al. (1987) interpreted these data as suggesting that in a substantial proportion of cases, the pathogenesis of ductal breast cancer involves the unmasking of a recessive locus on chromosome 13 and involvement of the same locus in heritable forms of this disease. Lundberg et al. (1987) raised the possibility of using molecular cytogenetics as an adjunct to histopathology in the diagnosis of breast tumors. ► ▼ BEHCET SYNDROME 109650 only shown in mice Mouth: Mouth ulcerations GU: Genital ulcerations; Epididymitis Skin: Erythema nodosum-like eruptions; Superficial thrombophlebitis; Pustular skin lesions; Hyperirritability; Raynaud phenomenon Hair: Alopecia areata Neuro: Brainstem syndrome; Meningoencephalomyelitic syndrome; Organic confusional state; Schizoaffective disorder Joints: Arthritis Eyes: Uveitis; Hypopyon; Iritis; Iridocyclitis; Choreoretinitis Inheritance: Familial cases reported, but probably not Mendelian CLINICAL FEATURES Goolamali et al. (1976) observed this syndrome of recurrent inflammatory lesions of the mouth, genitalia, and eyes in 5 persons in 4 generations of a family. Viral and autoimmune etiologies had been suggested. In the family reported, 2 brothers suffered from an unusual schizoaffective disorder and their mother, who also had Behcet syndrome, had severe alopecia areata, Raynaud phenomenon, and rheumatoid arthritis. Thus, this may be the familial aggregation recognized with other autoimmune diseases. Chamberlain (1978) found that first-degree relatives of patients with definite Behcet syndrome occasionally suffer from mouth and, less commonly, genital ulcerations, but not from uveitis and other features of severe disease. Spouses showed no abnormality. Mizuki et al. (1997) noted that Behcet disease is characterized by 4 major symptoms: oral aphthous ulcers, skin lesions, ocular symptoms, and genital ulcerations, and occasionally by inflammation in tissues and organs throughout the body, including the gastrointestinal tract, central nervous system, vascular system, lungs, and kidneys. Zamir et al. (2003) reported that in addition to oral and genital ulceration, conjunctival ulceration may also be found in patients with Behcet disease. This rare clinical sign, when accompanied by uveitis or orogenital ulcers, might suggest a diagnosis of Behcet disease. Yoshida et al. (2004) compared clinical findings in Japanese patients with Behcet disease examined in 2 decades (1980s and 1990s) to determine whether there had been a shift toward the appearance of less severe disease. Age of onset, type of inflammation, incidence of secondary glaucoma, and surgical history for glaucoma and cataract did not differ between the 1980s and 1990s. In patients seen in the 1990s, the number of ocular attacks per year and the percentage of patients treated with cyclosporine or cyclophosphamide decreased significantly. The percentage of eyes with good visual acuity (20/30 or better) increased, and the percentage of eyes with poor visual acuity (worse than 20/200) decreased significantly at both the first and the last examinations. There was a trend for less bilateral disease and fewer genital ulcers in the 1990s as well. BIOCHEMICAL FEATURES Serum proinflammatory cytokines upregulate leptin (164160) levels and leptin itself directly induces nitric oxide production from endothelial cells with its specific receptors. Evereklioglu et al. (2002) measured changes of serum leptin concentrations in 35 patients with Behcet syndrome compared with age- and sex-matched healthy volunteers by enzyme-linked immunosorbent assay. They also investigated whether disease activity or the duration of Behcet syndrome correlated with leptin concentration. The mean serum leptin concentrations in patients with Behcet syndrome were significantly higher than in healthy control volunteers. Active Behcet syndrome patients had significantly higher leptin concentrations when compared with patients in inactive periods. In addition, patients with longer disease duration had also significantly higher leptin concentrations than those with shorter disease duration. Evereklioglu et al. (2002) concluded that leptin may have a role in modulating endothelial function and may be involved in mechanisms for vessel endothelium repair, during an exacerbation as well as in chronic disease. Autoimmune response to retinal antigens is considered to be a cause of uveitis in Behcet disease. Okunuki et al. (2007) used proteomic techniques to compare retinal autoantigens recognized by sera from BD patients with uveitis or healthy donors. Six protein spots showing high reactivity with the serum from the BD patients were detected as candidate retinal autoantigens, and 3 of them were identified by mass spectrometry. Two of them had previously been identified as BD autoantigens, i.e., S-antigen (181031) and alpha-enolase (172130), and the other was selenium-binding protein (SELENBP1; 604188). Because anti-SELENBP1 antibody-positive patients showed more frequent ocular inflammation than the antibody-negative patient group, Okunuki et al. (2007) concluded that autoimmunity against this retinal antigen might contribute to the pathogenesis of uveitis in BD patients. INHERITANCE A positive family history was noted by Forbes and Robson (1960), Fowler et al. (1968), Mason and Barnes (1969), among others. Behcet disease is most frequent in Turkey and Japan. HLA-B5 has been found to predominate in cases. Dundar et al. (1985) reported 7 families with multiple cases. In 1 family, 3 sibs, including twins, were affected. Father and son were affected in another. They found HLA-B5 in the 3 families tested. Stewart (1986) analyzed 15 families from the U.K. and 9 from Turkey, finding 27 affected persons. There were no affected parents. The author concluded that the data were incompatible with a simple mendelian pattern of inheritance and specifically incompatible with autosomal recessive inheritance. No definite HLA association was found. Kone-Paut et al. (1999) conducted a retrospective study to analyze data collected from 572 patients with Behcet disease in whom the diagnosis was made with criteria defined by the International Study Group for BD. The age of 'attaining criteria,' i.e., the age at which the patient met the study group criteria, was evaluated for each patient. Recurrence risks were calculated for the pediatric group from information provided by 45 families. Of the 505 patients from whom the age of attaining criteria could be ascertained, 106 showed definitive BD before the age of 16 years and were considered pediatric patients with BD; the other 399 were classified as nonpediatric patients. Thirteen of the 106 pediatric patients (12.3%) and only 9 of the 399 nonpediatric patients (2.2%) had relatives affected by BD. This difference was significant (p less than 0.0001). Moreover, the mean age of attaining criteria in familial cases (17.95 years) was significantly lower than in sporadic cases (27.28 years). The recurrence risk among sibs and parents who had met the International Study Group criteria was 10%. Molinari et al. (2003) performed segregation analysis of 67 nuclear families with pediatric Behcet disease and 37 with nonpediatric Behcet disease according to the criteria established by the International Study Group for BD. They found data consistent with autosomal recessive inheritance in the families with pediatric Behcet disease (estimated mendelian segregation ratio = 0.248) but not in the nonpediatric families (estimated segregation ratio = 0.08). Molinari et al. (2003) stated that this was the first evidence of genetic heterogeneity in Behcet disease. MOLECULAR GENETICS Behcet disease is associated with the HLA-B51 molecule, which is relatively frequent, ranging from 45 to 60% in many different ethnic groups including Asian and Eurasian populations from Japan and the Middle East (Ohno et al., 1982). However, it was not certain whether HLA-B51 itself or a closely linked gene is responsible for susceptibility to Behcet disease. Mizuki et al. (1997) presented evidence that the primary association of Behcet disease may be not with HLA-B, but with polymorphism in the MICA gene (600169) located about 40 kb centromeric to the HLA-B gene. They discovered a triplet repeat (GCT/AGC) microsatellite polymorphism in the transmembrane region of the MICA gene. In investigations of 77 Japanese patients with Behcet disease, they found that the microsatellite allele of MICA consisting of 6 repetitions of GCT/AGC was present at significantly higher frequencies in the patient population (Pc = 0.00055) than in a control population. Furthermore, the (GCT/AGC)6 allele was present in all B51-positive patients and in an additional 13 B51-negative patients. These results suggested the possibility of a primary association of Behcet disease with MICA rather than HLA-B. Mizuki et al. (2000) studied the localization of the pathogenic gene of Behcet disease using microsatellite analysis of 3 different populations: Japanese, Greek, and Italian. In genotypic differentiation between patients and controls, the authors found that only HLA-B51 was significantly associated with BD in all 3 populations. These results suggested that the pathogenic gene of BD is HLA-B51 itself and not other genes located in the vicinity of HLA-B. ► ▼ TYPE 2 DIABETES MELLITUS; T2D 125853 only shown in mice Endo: Noninsulin-dependent diabetes mellitus Misc: Late onset Lab: Insulin resistance; Decreased glucose disposal Inheritance: Autosomal dominant A number sign (#) is used with this entry because of evidence that more than one gene locus is involved in the causation of noninsulin-dependent diabetes mellitus (NIDDM). See 601283 for description of a form of NIDDM linked to 2q, which may be caused by mutation in the gene encoding calpain-10 (CAPN10; 605286). See 601407 for description of a chromosome 12q locus, NIDDM2, found in a Finnish population. See 603694 for description of a locus on chromosome 20, NIDDM3. A mutation has been observed in hepatocyte nuclear factor-4-alpha (HNF4A; 600281.0004) in a French family with NIDDM of late onset. Mutations in the NEUROD1 gene (601724) on chromosome 2q32 were found to cause type II diabetes mellitus in 2 families. Mutation in the GLUT4 glucose transporter was associated with NIDDM in 1 patient (138190.0001) and in the GLUT2 glucose transporter in another (138160.0001). Mutation in the MAPK8IP1 gene, which encodes the islet-brain-1 protein, was found in a family with type II diabetes in individuals in 4 successive generations (604641.0001). Polymorphism in the KCNJ11 gene (600937.0014) confers susceptibility. In French white families, Vionnet et al. (2000) found evidence for a susceptibility locus for type II diabetes on 3q27-qter. They confirmed the diabetes susceptibility locus on 1q21-q24 reported by Elbein et al. (1999) in whites and by Hanson et al. (1998) in Pima Indians. A mutation in the GPD2 gene (138430.0001) on chromosome 2q24.1, encoding mitochondrial glycerophosphate dehydrogenase, was found in a patient with type II diabetes mellitus and in his glucose-intolerant half sister. Mutations in the PAX4 gene (167413) have been identified in patients with type II diabetes. Triggs-Raine et al. (2002) stated that in the Oji-Cree, a gly319-to-ser change in HNF1-alpha (142410.0008) behaves as a susceptibility allele for type II diabetes. Mutation in the HNF1B gene (189907.0007) was found in 2 Japanese patients with typical late-onset type II diabetes. Mutations in the IRS1 gene (147545) have been found in patients with type II diabetes. Reynisdottir et al. (2003) mapped a susceptibility locus for type II diabetes to chromosome 5q34-q35.2 (NIDDM4; 608036). A missense mutation in the AKT2 gene (164731.0001) caused autosomal dominant type II diabetes in 1 family. A (single-nucleotide polymorphism) SNP in the 3-prime untranslated region of the resistin gene (605565.0001) was associated with susceptibility to diabetes and to insulin resistance-related hypertension in Chinese subjects. Susceptibility to insulin resistance has been associated with polymorphism in the TCF1 (142410.0011), PPP1R3A (600917.0001), PTPN1 (176885.0001), ENPP1 (173335.0006), IRS1 (147545.0002), and EPHX2 (132811.0001) genes. The K121Q polymorphism of ENPP1 (173335.0006) is associated with susceptibility to type II diabetes; a haplotype defined by 3 SNPs of this gene, including K121Q, is associated with obesity, glucose intolerance, and type II diabetes. A SNP in the promoter region of the hepatic lipase gene (151670.0004) predicts conversion from impaired glucose tolerance to type II diabetes. Variants of transcription factor 7-like-2 (TCF7L2; 602228.0001), located on 10q, have also been found to confer risk of type II diabetes. A common sequence variant, dbSNP rs10811661, on chromosome 9p21 near the CDKN2A (600160) and CDKN2B (600431) genes has been associated with risk of type II diabetes. Variation in the PPARG gene (601487) has been associated with risk of type 2 diabetes. A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to NIDDM. Variation in the KCNJ15 gene (602106) has been associated with T2DM in lean Asians. Noninsulin-dependent diabetes mellitus is distinct from MODY (606391) in that it is polygenic, characterized by gene-gene and gene-environment interactions with onset in adulthood, usually at age 40 to 60 but occasionally in adolescence if a person is obese. The pedigrees are rarely multigenerational. The penetrance is variable, possibly 10 to 40% (Fajans et al., 2001). Persons with type II diabetes usually have an obese body habitus and manifestations of the so-called metabolic syndrome (see 605552), which is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia. INHERITANCE In 3 families with MODY and 7 with 'common' type II diabetes mellitus, O'Rahilly et al. (1992) excluded linkage to the INS locus (176730). Exclusive of the mendelian forms of NIDDM represented by MODY, the high incidence of diabetes in certain populations and among first-degree relatives of type II diabetic patients, as well as the high concordance in identical twins, provides strong evidence that genetic factors underlie susceptibility to the common form of NIDDM which affects up to 6% of the United States population. Although defects in both insulin secretion and insulin action may be necessary for disease expression in groups with a high incidence of NIDDM, such as offspring of type II diabetic parents and Pima Indians, insulin resistance and decreased glucose disposal can be shown to precede and predict the onset of diabetes (Martin et al., 1992; Bogardus et al., 1989). In both of these groups, relatives and Pima Indians, there is evidence of familial clustering of insulin sensitivity. Thus, insulin resistance appears to be a central feature of NIDDM and may be an early and inherited marker of the disorder. Martinez-Marignac et al. (2007) analyzed and discussed the use of admixture mapping of type 2 diabetes genetic risk factors in Mexico City. Type 2 diabetes is at least twice as prevalent in Native American populations as in populations of European ancestry. The authors characterized the admixture proportions in a sample of 286 unrelated type 2 diabetes patients and 275 controls from Mexico City. Admixture proportions were estimated using 69 autosomal ancestry-informative markers (AIMs). The average proportions of Native American, European, and West African admixture were estimated as 65%, 30%, and 5%, respectively. The contributions of Native American ancestors to maternal and paternal lineages were estimated as 90% and 40%, respectively. In a logistic model with higher educational status as dependent variable, the odds ratio for higher educational status associated with an increase from 0 to 1 in European admixture proportions was 9.4. This association of socioeconomic status with individual admixture proportion showed that genetic stratification in this population is paralleled, and possibly maintained, by socioeconomic stratification. The effective number of generations back to unadmixed ancestors was 6.7, from which Martinez-Marignac et al. (2007) could estimate the number of evenly distributed AIMs required to localize genes underlying disease risk between populations of European and Native American ancestry, i.e., about 1,400. Sample sizes of about 2,000 cases would be required to detect any locus that contributed an ancestry risk ratio of at least 1.5. Kong et al. (2009) found 3 SNPs at 11p15 that had association with type 2 diabetes and parental origin specific effects; These were dbSNP rs2237892, dbSNP rs231362, and dbSNP rs2334499. For dbSNP rs2334499 the allele that confers risk when paternally inherited (T) is protective when maternally inherited. BIOCHEMICAL FEATURES A subgroup of patients diagnosed with type II diabetes have circulating antibodies to islet cell cytoplasmic antigens, most frequently to glutamic acid decarboxylase (see GAD2; 138275). Among 1,122 type II diabetic patients, Tuomi et al. (1999) found GAD antibody in 9.3%, a significantly higher prevalence than that found in patients with impaired glucose tolerance or in controls. The GADab+ patients had lower fasting C-peptide concentration, lower insulin response to oral glucose, and higher frequency of the high-risk HLA-DQB10201/0302 (see 604305) genotype (though significantly lower than in patients with type I diabetes) when compared with GADab- patients. Tuomi et al. (1999) suggested the designation latent autoimmune diabetes in adults (LADA) to define the subgroup of type II diabetes patients with GADab positivity (greater than 5 relative units) and age at onset greater than 35 years. Both defective insulin secretion and insulin resistance have been reported in relatives of NIDDM subjects. Elbein et al. (1999) tested 120 members of 26 families containing an NIDDM sib pair with a tolbutamide-modified, frequently sampled intravenous glucose tolerance test to determine the insulin sensitivity index (SI) and acute insulin response to glucose (AIRglucose). Both SI x AIRglucose and SI showed strong negative genetic correlations with diabetes (-85 +/- 3% and -87 +/- 2%, respectively, for all family members), whereas AIRglucose did not correlate with diabetes. The authors concluded that insulin secretion, as measured by SI x AIRglucose, is decreased in nondiabetic members of familial NIDDM kindreds; that SI x AIRglucose in these high-risk families is highly heritable; and that the same polygenes may determine diabetes status and a low SI x AIRglucose. They also suggested that insulin secretion, when expressed as an index normalized for insulin sensitivity, is more familial than either insulin sensitivity or first-phase insulin secretion alone, and may be a very useful trait for identifying genetic predisposition to NIDDM. GENOTYPE/PHENOTYPE CORRELATIONS Li et al. (2001) assessed the prevalence of families with both type I and type II diabetes in Finland and studied, in patients with type II diabetes, the association between a family history of type 1 diabetes, GAD antibodies (GADab), and type I diabetes-associated HLA-DQB1 genotypes. Further, in mixed type I/type II diabetes families, they investigated whether sharing an HLA haplotype with a family member with type I diabetes influenced the manifestation of type II diabetes. Among 695 families with more than 1 patient with type II diabetes, 100 (14%) also had members with type I diabetes. Type II diabetic patients from the mixed families more often had GADab (18% vs 8%) and DQB10302/X genotype (25% vs 12%) than patients from families with only type II diabetes; however, they had a lower frequency of DQB102/0302 genotype compared with adult-onset type I patients (4% vs 27%). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA10501-DQB102 or DR40401/4-DQA10301-DQB10302, compared with patients without such haplotypes. This finding was independent of the presence of GADab. The authors concluded that type I and type II diabetes cluster in the same families. A shared genetic background with a patient with type I diabetes predisposes type II diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. Their findings also supported a possible genetic interaction between type I and type II diabetes mediated by the HLA locus. CLINICAL MANAGEMENT Fonseca et al. (1998) studied the effects of troglitazone monotherapy on glycemic control in patients with NIDDM in 24 hospital and outpatient clinics in the U.S. and Canada. Troglitazone 100, 200, 400, or 600 mg, or placebo, was administered once daily with breakfast to 402 patients with NIDDM and fasting serum glucose (FSG) greater than 140 mg/dL, glycosylated hemoglobin (HbA1c) greater than 6.5%, and fasting C-peptide greater than 1.5 ng/mL. Patients treated with 400 and 600 mg troglitazone had significant decreases from baseline in mean FSG (-51 and -60 mg/dL, respectively) and HbA1c (-0.7% and -1.1%, respectively) at month 6 compared to placebo-treated patients. In the diet-only subset, 600 mg troglitazone therapy resulted in a significant (P less than 0.05) reduction in HbA1c (-1.35%) and a significant reduction in FSG (-42 mg/dL) compared with placebo. Patients previously treated with sulfonylurea therapy had significant (P less than 0.05) decreases in mean FSG with 200 to 600 mg troglitazone therapy compared with placebo (-48, -61, and -66 mg/dL, respectively). The authors concluded that troglitazone monotherapy significantly improves HbA1c and fasting serum glucose, while lowering insulin and C-peptide in patients with NIDDM. Chung et al. (2000) studied the effect of HMG-CoA reductase inhibitors on bone mineral density (BMD) of type II diabetes mellitus by a retrospective review of medical records. In the control group, BMD of the spine significantly decreased after 14 months. In the treatment group, BMD of the femoral neck significantly increased after 15 months. In male subjects treated with HMG-CoA reductase inhibitors, there was a significant increase in BMD of the femoral neck and femoral trochanter, but in female subjects, only BMD of the femoral neck increased. The authors concluded that HMG-CoA reductase inhibitors may increase BMD of the femur in male patients with type II diabetes mellitus. Aljada et al. (2001) investigated the effect of troglitazone on the proinflammatory transcription factor NF-kappa-B (see 164011) and its inhibitory protein I-kappa-B (see 164008) in mononuclear cells (MNC) in obese patients with type II diabetes. Seven obese patients with type II diabetes were treated with troglitazone (400 mg/day) for 4 weeks, and blood samples were obtained at weekly intervals. NF-kappa-B binding activity in MNC nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to be inhibited up to week 4. On the other hand, I-kappa-B protein levels increased significantly after troglitazone treatment at week 1, and this increase persisted throughout the study. The authors concluded that troglitazone has profound antiinflammatory effects in addition to antioxidant effects in obese type II diabetics, and that these effects may be relevant to the beneficial antiatherosclerotic effects of troglitazone at the vascular level. In a multicenter, double-blind trial, Garber et al. (2003) enrolled patients with type II diabetes who had inadequate glycemic control (glycosylated hemoglobin A1C greater than 7% and less than 12%) with diet and exercise alone to compare the benefits of initial therapy with glyburide/metformin tablets versus metformin or glyburide monotherapy. They randomized 486 patients to receive glyburide/metformin tablets, metformin, or glyburide. Changes in A1C, fasting plasma glucose, fructosamine, serum lipids, body weight, and 2-hour postprandial glucose after a standardized meal were assessed after 16 weeks of treatment. Glyburide/metformin tablets caused a superior mean reduction in A1C from baseline versus metformin and glyburide monotherapy. Glyburide/metformin also significantly reduced fasting plasma glucose and 2-hour postprandial glucose values compared with either monotherapy. The final mean doses of glyburide/metformin were lower than those of metformin and glyburide. The authors concluded that first-line treatment with glyburide/metformin tablets provided superior glycemic control over component monotherapy, allowing more patients to achieve American Diabetes Association treatment goals with lower component doses in drug-naive patients with type II diabetes. PATHOGENESIS Piatti et al. (2000) compared resistance to insulin-mediated glucose disposal and plasma concentrations of nitric oxide (NO) and cGMP in 35 healthy volunteers with, or 27 without, at least 1 sib and 1 parent with type II diabetes. The mean insulin sensitivity index (ISI) was significantly greater in those without a family history as compared with nondiabetic volunteers with a family history of type II diabetes, whether they had normal glucose tolerance or impaired glucose tolerance. In addition, basal NO levels, evaluated by the measurement of its stable end products (i.e., nitrite and nitrate levels, NO2-/NO3-) were significantly higher, and levels of cGMP, its effector messenger, were significantly lower in those with a family history, irrespective of their degree of glucose tolerance, when compared with healthy volunteers without a family history of type II diabetes. Furthermore, when the 62 volunteers were analyzed as 1 group, there was a negative correlation between ISI and NO2-/NO3- levels and a positive correlation between ISI and cGMP levels. The authors concluded that alterations of the NO/cGMP pathway seem to be an early event in nondiabetic individuals with a family history of type II diabetes, and that these changes are correlated with the degree of insulin resistance. To investigate how insulin resistance arises, Petersen et al. (2003) studied 16 healthy, lean elderly aged 61 to 84 and 13 young participants aged 18 to 39 matched for lean body mass (BMI less than 25) and fat mass assessed by DEXA (dual energy X-ray absorptiometry) scanning, and activity level. Elderly study participants were markedly insulin-resistant as compared with young controls, and this resistance was attributable to reduced insulin-stimulated muscle glucose metabolism. These changes were associated with increased fat accumulation in muscle and liver tissue, assessed by NMR spectroscopy, and with an approximately 40% reduction in mitochondrial oxidative and phosphorylation activity, as assessed by in vivo NMR spectroscopy. Petersen et al. (2003) concluded that their data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly. Petersen et al. (2004) performed glucose clamp studies in healthy, young, lean, insulin-resistant offspring of patients with type II diabetes and insulin-sensitive subjects matched for age, height, weight, and physical activity. The insulin-stimulated rate of glucose uptake by muscle was approximately 60% lower in insulin-resistant subjects than in controls (p less than 0.001) and was associated with an increase of approximately 80% in intramyocellular lipid content (p less than 0.005). The authors attributed the latter increase to mitochondrial dysfunction, noting a reduction of approximately 30% in mitochondrial phosphorylation (p = 0.01 compared to controls). Petersen et al. (2004) concluded that insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type II diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation. Do et al. (2005) assessed the correlation between persistent diabetic macular edema and hemoglobin A1c (HbA1C). Patients with type II diabetes and persistent clinically significant macular edema had higher HbA1C at the time of their disease than patients with resolved macular edema. Patients with bilateral disease had more elevated HbA1C than those with unilateral disease. Foti et al. (2005) reported 4 patients with insulin resistance and type II diabetes in whom cell-surface insulin receptors were decreased and INSR (147670) gene transcription was impaired, although the INSR genes were normal. In these individuals, expression of HMGA1 (600701) was markedly reduced; restoration of HMGA1 protein expression in their cells enhanced INSR gene transcription and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Foti et al. (2005) concluded that defects in HMGA1 may cause decreased insulin receptor expression and induce insulin resistance. Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT; 300255). Dentin et al. (2008) showed that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cAMP response element-binding protein (CREB) 2 (TORC2 or CRTC2; 608972). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase (604039) blocked effects of glucose on gluconeogenesis, demonstrating the importance of the hexosamine biosynthetic pathway in the development of glucose intolerance. MAPPING In an autosomal genome screen in 363 nondiabetic Pima Indians at 516 polymorphic microsatellite markers, Pratley et al. (1998) found a suggestion of linkage at several chromosomal regions with particular characteristics known to be predictive of NIDDM: 3q21-q24, linked to fasting plasma insulin concentration and in vivo insulin action; 4p15-q12, linked to fasting plasma insulin concentration; 9q21, linked to 2-hour insulin concentration during oral glucose tolerance testing; and 22q12-q13, linked to fasting plasma glucose concentration. None of the linkages exceeded a lod score of 3.6 (a 5% probability of occurring in a genomewide screen). In 719 Finnish sib pairs with type II diabetes, Ghosh et al. (2000) performed a genome scan at an average resolution of 8 cM. The strongest results were for chromosome 20, where they observed a weighted maximum lod score of 2.15 at map position 69.5 cM from pter, and secondary weighted lod score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. The next largest maximum lod score was for chromosome 11 (maximum lod score = 1.75 at 84.0 cM), followed by chromosomes 2, 10, and 6. When they conditioned on chromosome 2 at 8.5 cM, the maximum lod score for chromosome 20 increased to 5.50 at 69.0 cM. Watanabe et al. (2000) reported results from an autosomal genome scan for type II diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sib pair and analyzed by the variance components-based quantitative-trait locus linkage approach. In diabetic individuals, the strongest results were observed on chromosomes 3 and 13. Integrating genome scan results of Ghosh et al. (2000), they identified several regions that may harbor susceptibility genes for type II diabetes in the Finnish population. In a genomewide scan of 359 Japanese individuals with type II diabetes from 159 families, including 224 affected sib pairs, Mori et al. (2002) found suggestive linkage at chromosome 11p13-p12, with a maximum lod score of 3.08. Analysis of sib pairs who had a BMI of less than 30 revealed suggestive linkage at chromosomes 7p22-p21 and 11p13-p12 (lod scores of 3.51 and 3.00, respectively). Analysis of sib pairs who were diagnosed before the age of 45 revealed suggestive linkage at chromosome 15q13-q21, with a maximum lod score of 3.91. Demenais et al. (2003) applied the genome search metaanalysis (GSMA) method to genomewide scans conducted with 4 European type II diabetes mellitus cohorts comprising a total of 3,947 individuals, 2,843 of whom were affected. The analysis provided evidence for linkage of type II diabetes to 6 regions, with the strongest evidence on chromosome 17p11.2-q22 (p = 0.0016), followed by 2p22.1-p13.2 (p = 0.027), 1p13.1-q22 (p = 0.028), 12q21.1-q24.12 (p = 0.029), 6q21-q24.1 (p = 0.033), and 16p12.3-q11.2 (p = 0.033). Linkage analysis of the pooled raw genotype data generated maximum lod scores in the same regions as identified by GSMA; the maximum lod score for the 17p11.2-q22 region was 1.54. Using nonparametric linkage analyses, Van Tilburg et al. (2003) performed a genomewide scan to find susceptibility loci for type II diabetes mellitus in the Dutch population. They studied 178 families from the Netherlands, who constituted 312 affected sib pairs. Because obesity and type II diabetes mellitus are interrelated, the dataset was stratified for the subphenotype BMI, corrected for age and gender. This resulted in a suggestive maximum multipoint lod score of 2.3 (single-point P value, 9.7 x 10(-4); genomewide P value, 0.028) for the most obese 20% pedigrees of the dataset, between marker loci D18S471 and D18S843. In the lowest 80% obese pedigrees, 2 interesting loci on chromosome 2 and 19 were found, with lod scores of 1.5 and 1.3. Shtir et al. (2007) performed ordered subset analysis on affected individuals from 2 sets of families ascertained on affected sib pairs with type 2 diabetes mellitus and found that 33 families with the lowest average fasting insulin (606035) showed evidence for linkage to a locus on chromosome 6q (maximum lod score of 3.45 at 128 cM near D6S1569, uncorrected p = 0.017) that was coincident with QTL linkage results for fasting and 2-hour insulin levels in family members without type 2 diabetes mellitus. The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. Case-control comparisons identified 3 significant independent association signals for type 2 diabetes, at dbSNP rs9465871 on chromosome 6p22, dbSNP rs4506565 on chromosome 10q25, and dbSNP rs9939609 on chromosome 16q12. In a genomewide association study of 1,363 French type 2 diabetes cases and controls, Sladek et al. (2007) confirmed the known association with dbSNP rs7903146 of the TCF7L2 gene (602228.0001) on chromosome 10q25.2 (p = 3.2 x 10(-17)). They also found significant association between T2D and 2 SNPs on chromosome 10q23.33 (dbSNP rs1111875 and dbSNP rs7923837), located near the telomeric end of a 270-kb linkage disequilibrium block containing the IDE (146680), HHEX (604420), KIF11 (148760) genes. Sladek et al. (2007) stated that fine mapping of the HHEX locus and biologic studies would be required to identify the causative variant. The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007) analyzed 386,731 common SNPs in 1,464 patients with type 2 diabetes and 1,467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators Finland-United States Investigation of NIDDM Genetics (FUSION) and Wellcome Trust Case Control Consortium/United Kingdom Type 2 Diabetes Genetics Consortium (WTCCC/UKT2D), this group identified and confirmed 3 loci associated with type 2 diabetes--in a noncoding region near CDKN2A (600160) and CDKN2B (600431), in an intron of IGF2BP2 (608289), and in an intron of CDKAL1 (611259)--and replicated associations near HHEX and SLC30A8 (611145) by recent whole-genome association study. The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007) identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The authors concluded that the discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genomewide association studies to provide potentially important clues to the pathogenesis of common diseases. Adopting a genomewide association strategy, Scott et al. (2007) genotyped 1,161 Finnish type 2 diabetes cases and 1,174 Finnish normal glucose tolerant controls with greater than 315,000 SNPs and imputed genotypes for an additional greater than 2 million autosomal SNPs. Scott et al. (2007) carried out association analysis with these SNPs to identify genetic variants that predispose to type 2 diabetes, compared to their type 2 diabetes association results with the results of 2 similar studies, and genotyped 80 SNPs in an additional 1,215 Finnish type 2 diabetes cases and 1,258 Finnish normal glucose tolerant controls. Scott et al. (2007) identified type 2 diabetes-associated variants in an intergenic region of chromosome 11p12, contributed to the identification of type 2 diabetes-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirmed that variants near TCF7L2, SLC30A8, HHEX, FTO (610966), PPARG (601487), and KCNJ11 (600937) are associated with type 2 diabetes risk. Scott et al. (2007) concluded that this brings the number of type 2 diabetes loci now confidently identified to at least 10. Starting from genomewide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, Zeggini et al. (2007) set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls and by integration of their findings with equivalent data from other international consortia. Zeggini et al. (2007) detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed associations at HHEX/IDE and at SLC30A8. Zeggini et al. (2007) concluded that their findings provided insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes. Van Vliet-Ostaptchouk et al. (2008) genotyped 501 unrelated Dutch patients with type 2 diabetes and 920 healthy controls for 2 SNPs in strong linkage disequilibrium near the HHEX gene, dbSNP rs7923837 and dbSNP rs1111875, and found that for both SNPs, the risk for T2D was significantly increased in carriers of the major alleles (OR of 1.57 and p = 0.017; OR of 1.68 and p = 0.003, respectively). Assuming a dominant genetic model, the population-attributable risks for diabetes due to the at-risk alleles of dbSNP rs7923837 and dbSNP rs1111875 were estimated to be 33% and 36%, respectively. Gudmundsson et al. (2007) found that the A allele of dbSNP rs4430796 in the HNF1B gene (189907) was associated with a protective effect against type 2 diabetes in a study of 1,380 Icelandic patients and 9,940 controls, and in 7 additional type 2 diabetes case-control groups of European, African, and Asian ancestry (p = 2.7 x 10(-7) and odds ratio of 0.91, for the combined results). This SNP is also associated with prostate cancer risk (see HPC11, 611955). Prokopenko et al. (2008) reviewed advances in identifying common genetic variants that contribute to complex multifactorial phenotypes such as type 2 diabetes (T2D), particularly the ability to perform genomewide association studies in large samples. They noted that the 2 most robust T2D candidate-gene associations previously reported, for common polymorphisms in PPARG and KCNJ11, have only modest effect sizes, with each copy of the susceptibility allele increasing the risk of disease by 15 to 20%. In contrast, microsatellite mapping detected an association with variation in the TCF7L2 gene that has a substantially stronger effect, with the 10% of Europeans who are homozygous for the risk allele having approximately twice the odds of developing T2D compared to those carrying no copies of the risk allele. Prokopenko et al. (2008) stated that about 20 common variants had been robustly implicated in T2D susceptibility to date, but noted that for most of the loci, causal variants had yet to be identified with any certainty. The Wellcome Trust Case Control Consortium (2010) undertook a large direct genomewide study of association between copy number variants (CNVs) and 8 common human diseases involving approximately 19,000 individuals. Association testing and follow-up replication analyses confirmed association of CNV at the TSPAN8 (600769) locus with type 2 diabetes. - Association with Variation in KCNQ1 Yasuda et al. (2008) carried out a multistage genomewide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1 (607542), and dense mapping within the gene revealed that dbSNP rs2237892 in intron 15 showed the lowest P value (6.7 x 10(-13), odds ratio = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese, and European ancestry as well as in 2 independent Japanese populations, and metaanalysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (odds ratio = 1.40; 95% confidence interval = 1.34-1.47) for dbSNP rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Unoki et al. (2008) conducted a genomewide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 to be a strong candidate for conferring susceptibility to type 2 diabetes. Unoki et al. (2008) detected consistent association of a SNP in KCNQ1 (dbSNP rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 x 10(-12); odds ratio = 1.26, 95% confidence interval = 1.18-1.34). Several other SNPs in the same linkage disequilibrium block were strongly associated with type 2 diabetes. The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean and Danish populations. - Association with Variation in SHBG Ding et al. (2009) analyzed levels of sex hormone-binding globulin (see SHBG; 182205) in 359 women newly diagnosed with type 2 diabetes and 359 female controls and found that higher plasma levels of SHBG were prospectively associated with a lower risk of type 2 diabetes, with multivariable odds ratios ranging from 1.00 for the lowest quartile of plasma levels to 0.09 for the highest quartile; the results were replicated in an independent cohort of men (p less than 0.001 for results in both women and men). Ding et al. (2009) identified an SHBG SNP, dbSNP rs6259, that was associated with a 10% higher plasma level of SHBG, and another SNP, dbSNP rs6257, that was associated with a 10% lower plasma level of SHBG; variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated SHBG levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard deviation increase in plasma level of SHBG was 0.28 among women and 0.29 among men. Ding et al. (2009) suggested that variation in the SHBG gene on chromosome 17p13-p12 may have a causal role in the risk of type 2 diabetes. Kong et al. (2009) identified a differentially methylated CTCF binding site at 11p15 and demonstrated correlation of dbSNP rs2334499 with decreased methylation of that site. The CTCF-binding site is OREG0020670 and its 2-kb region located 17 kb centromeric to the type 2 diabetes marker dbSNP rs2334499. Perry et al. (2010) genotyped 27,657 type 2 diabetes patients and 58,481 controls from 15 studies at the SHBG promoter SNP dbSNP rs1799941 that is strongly associated with serum levels of SHBG. The authors used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The dbSNP rs1799941 variant was associated with type 2 diabetes (OR, 0.94; 95% CI, 0.91-0.97; p = 2 x 10(-5)), with the SHBG-raising A allele associated with reduced risk of type 2 diabetes, the results were very similar in men and women. There was no evidence that dbSNP rs1799941 was associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. MOLECULAR GENETICS - Mutation in PPAR-Gamma Altshuler et al. (2000) confirmed an association of the common pro12-to-ala polymorphism in PPAR-gamma (601487.0002) with type II diabetes. They found a modest but significant increase in diabetes risk associated with the more common proline allele (approximately 85% frequency). Because the risk allele occurs at such high frequency, its modest effect translates into a large population-attributable risk--influencing as much as 25% of type II diabetes in the general population. Savage et al. (2002) described a family, which they referred to as a 'Europid pedigree,' in which several members had severe insulin resistance. The grandparents had typical late-onset type II diabetes with no clinical features of severe insulin resistance. Three of their 6 children and 2 of their grandchildren had acanthosis nigricans, elevated fasting plasma insulin levels. Hypertension was also a feature. By mutation screening, Savage et al. (2002) identified a heterozygous frameshift resulting in a premature stop mutation of the PPARG (601487.0011) gene which was present in the grandfather, all 5 relatives with severe insulin resistance, and 1 other relative with normal insulin levels. Further candidate gene studies revealed a heterozygous frameshift/premature stop mutation in PPP1R3A (600917.0003) which was present in the grandmother, in all 5 individuals with severe insulin resistance, and in 1 other relative. Thus, all 5 family members with severe insulin resistance, and no other family members, were double heterozygotes with respect to frameshift mutations. (Although the article by Savage et al. (2002) originally stated that the affected individuals were compound heterozygotes, they were actually double heterozygotes. Compound heterozygosity is heterozygosity at the same locus for each of 2 different mutant alleles; double heterozygosity is heterozygosity at each of 2 separate loci. The use of an incorrect term in the original publication was the result of a 'copy-editing error that was implemented after the authors returned corrected proofs' (Savage et al., 2002).) - Association with Insulin Receptor Substrate-2 Mammarella et al. (2000) genotyped 193 Italian patients with type II diabetes and 206 control subjects for the insulin receptor substrate-2 G1057D polymorphism (600797.0001). They found evidence for a strong association between type II diabetes and the polymorphism, which appears to be protective against type II diabetes in a codominant fashion. - Association with Adiponectin For a discussion of an association between variation in the ADIPOQ gene (605441) on chromosome 3q27 and type 2 diabetes, see ADIPQTL1 (612556). - Association with Mitochondrial DNA Variation A common mtDNA variant (T16189C) in a noncoding region of mtDNA was positively correlated with blood fasting insulin by Poulton et al. (1998). Poulton et al. (2002) demonstrated a significant association between the 16189 variant and type II diabetes in a population-based case-control study in Cambridgeshire, UK (n = 932, odds ratio = 1.61; 1.0-2.7, P = 0.048), which was greatly magnified in individuals with a family history of diabetes from the father's side (odds ratio = infinity; P less than 0.001). Poulton et al. (2002) demonstrated that the 16189 variant had arisen independently many times and on multiple mitochondrial haplotypes. They speculated that the 16189 variant may alter mtDNA bending and hence could influence interactions with regulatory proteins which control replication or transcription. Mohlke et al. (2005) presented data supporting previous evidence for association of 16189T-C with reduced ponderal index at birth and also showed evidence for association with reduced birthweight but not with diabetes status. This study suggested that mitochondrial genome variants may play at most a modest role in glucose metabolism in the Finnish population studied. Furthermore, the data did not support a reported maternal inheritance pattern of type II diabetes mellitus but instead showed a strong effect of recall bias. Because mitochondria play pivotal roles in both insulin secretion from the pancreatic beta cells and insulin resistance of skeletal muscles, Fuku et al. (2007) performed a large-scale association study to identify mitochondrial haplogroups that may confer resistance against or susceptibility to type II diabetes mellitus. The study population comprised 2,906 unrelated Japanese individuals, including 1,289 patients with type II diabetes mellitus and 1,617 controls, and 1,365 unrelated Korean individuals, including 732 patients with type II diabetes and 633 controls. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups. Multivariate logistic regression analysis with adjustment for age and sex revealed that the mitochondrial group N9a was significantly associated with resistance against type II diabetes mellitus (P = 0.0002) with an odds ratio of 0.55 (95% confidence interval 0.40-0.75). Even in the modern environment, which is often characterized by satiety and physical inactivity, this haplotype might confer resistance against type II diabetes mellitus. The N9a haplogroup found to be associated with reduced susceptibility to type II diabetes mellitus by Fuku et al. (2007) consisted of a synonymous SNP in ND2 (516001), 5231G-A; a missense change in ND5 (516005), thr8 to ala; and a synonymous change also in ND5, 12372G-A. - Mutation in PAX4 Shimajiri et al. (2001) scanned the PAX4 gene (167413) in 200 unrelated Japanese probands with type 2 diabetes and identified an arg121-to-tyr mutation (R121W; 167413.0001) in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects (p = 0.01). Six of 7 patients had a family history of diabetes or impaired glucose tolerance, and 4 of 7 had transient insulin therapy at the onset. One of them, a homozygous carrier, had relatively early-onset diabetes and slowly fell into an insulin-dependent state without an autoimmune-mediated process. - Association with TFAP2B Maeda et al. (2005) performed a genomewide, case-control association study using gene-based SNPs in Japanese patients with type II diabetes and controls and identified several variations within the TFAP2B gene (601601) that were significantly associated with type II diabetes: an intron 1 VNTR (p = 0.0009), intron 1 +774G-T (p = 0.0006), and intron 1 +2093A-C (p = 0.0004). The association of TFAP2B with type II diabetes was also observed in a U.K. population. Maeda et al. (2005) suggested that the TFAP2B gene may confer susceptibility to type II diabetes. - Mutation in ABCC8 Babenko et al. (2006) screened the ABCC8 gene (600509) in 34 patients with permanent neonatal diabetes (606176) or transient neonatal diabetes (see 601410) and identified heterozygosity for 7 missense mutations in 9 patients (see, e.g., 600509.0017-600509.0020). The mutation-positive fathers of 5 of the probands with transient neonatal diabetes developed type II diabetes mellitus in adulthood; Babenko et al. (2006) proposed that mutations of the ABCC8 gene may give rise to a monogenic form of type II diabetes with variable expression and age at onset. - Association with WFS1 Domenech et al. (2002) performed mutation screening of the WFS1 gene (606201) in 23 patients with NIDDM and sensorineural deafness, 48 patients with autosomal recessive deafness, and 38 patients with NIDDM. Three different missense mutations were found in heterozygosity in 4 unrelated patients: 3 with diabetes mellitus and deafness and 1 with deafness. In the family of the deaf patient, the mutation was also found in the deaf sister and in her unaffected father. The mutations found were located in the intracytoplasmic domain of the protein and were not detected among 49 healthy controls. Sandhu et al. (2007) conducted a gene-centric association study for type 2 diabetes in multiple large cohorts and identified 2 SNPs located in the WFS1 gene, dbSNP rs10010131 (606201.0021) and dbSNP rs6446482 (602201.0022), that were strongly associated with diabetes risk (P = 1.4 x 10(-7) and P = 3.4 x 10(-7), respectively, in the pooled study set). The risk allele was the major allele for both SNPs, with a frequency of 60% for both. The authors noted that both are intronic, with no obvious evidence for biologic function. - Association with IL6 Mohlig et al. (2004) investigated the IL6 -174C-G SNP (147620.0001) and development of NIDDM. They found that this SNP modified the correlation between BMI and IL6 by showing a much stronger increase of IL6 at increased BMI for CC genotypes compared with GG genotypes. The -174C-G polymorphism was found to be an effect modifier for the impact of BMI regarding NIDDM. The authors concluded that obese individuals with BMI greater than or equal to 28 kg/m2 carrying the CC genotype showed a more than 5-fold increased risk of developing NIDDM compared with the remaining genotypes and, hence, might profit most from weight reduction. Illig et al. (2004) investigated the association of the IL6 SNPs C-174G and A-598G on parameters of type II diabetes and the metabolic syndrome in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. Both -174G and -598G alleles were significantly associated with type 2 diabetes (-174G: odds ratio = 1.51, 95% CI = 1.11-2.07, P = 0.0096; -598G: odds ratio = 1.56, 95% CI = 1.13-2.15, P = 0.0069), but not with impaired glucose tolerance. In subgroup analyses, the association reached statistical significance in men and in leaner subjects (BMI less than 28.7 kg/m2, i.e., study median) but not in women or more obese persons. Circulating IL6 levels were not associated with the IL6 polymorphisms, but significantly elevated levels of the chemokine monocyte chemoattractant protein-1 (MCP1; 158105)/CC chemokine ligand-2 (CKR2; 601267) in carriers of the protective genotypes indicated an indirect effect of these SNPs on the innate immune system. - Association with KCNJ15 Okamoto et al. (2010) identified a synonymous SNP (dbSNP rs3746876, C566T) in exon 4 of the KCNJ15 (602106) that showed significant association with type 2 diabetes mellitus affecting lean individuals in 3 independent Japanese sample sets (p = 2.5 x 10(-7); odds ratio, 2.54) and with unstratified T2DM (p = 6.7 x 10(-6); OR, 1.76). The diabetes risk allele frequency was, however, very low among Europeans and no association between the variant and T2DM could be shown in a Danish case-control study. Functional analysis in HEK293 cells demonstrated that the risk T allele increased KCNJ15 expression via increased mRNA stability, which resulted in higher expression of protein compared to the C allele. OTHER FEATURES Diabetes mellitus is a recognized consequence of hereditary hemochromatosis (HFE; 235200). To test whether common mutations in the HFE gene (613609) that associate with this condition and predispose to increases in serum iron indices are overrepresented in diabetic populations, Halsall et al. (2003) determined the allele frequencies of the C282Y (613609.0001) and H63D (613609.0002) HFE mutations among a cohort of 552 patients with typical type II diabetes mellitus. There was no evidence for overrepresentation of iron-loading HFE alleles in type II diabetes mellitus, suggesting that screening for HFE mutations in this population is of no value. Meigs et al. (2008) genotyped SNPs at 18 loci associated with diabetes in 2,377 participants of the Framingham Offspring Study. They created a genotype score from the number of risk alleles and used logistic regression to generate C statistics indicating the extent to which the genotype score can discriminate the risk of diabetes when used alone and in addition to clinical risk factors. There were 255 new cases of diabetes during 28 years of follow-up. The mean (+/- standard deviation) genotype score was 17.7 +/- 2.7 among subjects in whom diabetes developed and 17.1 +/- 2.6 among those in whom diabetes did not develop (P = less than 0.001). The sex-associated odds ratio for diabetes was 1.12 per risk allele (95% confidence interval, 1.07 to 1.17). The C statistic was 0.534 without the genotype score and 0.581 with the score (P = 0.01). In a model adjusted for age, sex, family history, body mass index, fasting glucose level, systolic blood pressure, high-density lipoprotein cholesterol level, and triglyceride level, the C statistic was 0.900 without the genotype score and 0.901 with the score, not significantly different. The genotype score resulted in the appropriate risk reclassification of, at most, 4% of the subjects. Meigs et al. (2008) concluded that a genotype score based on 18 risk alleles predicted new cases of diabetes in the community but provided only a slightly better prediction of risk than knowledge of common risk factors alone. Lyssenko et al. (2008) genotyped 16 SNPs and examined clinical factors in 16,061 Swedish and 2,770 Finnish subjects. Type 2 diabetes developed in 2,201 (11.7%) of these subjects during a median follow-up period of 23.5 years. Strong predictors of diabetes were a family history of the disease, increased body mass index, elevated liver enzyme levels, current smoking status, and reduced measures of insulin secretion action. Variants in 11 genes were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic (also known as C statistics) curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P = 1.0 x 10(-4)). Lyssenko et al. (2008) concluded that as compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up. ANIMAL MODEL The most widely used animal model of nonobese NIDDM is the Goto-Kakizaki (GK) rat. Galli et al. (1996) mapped 3 independent loci involved in the disease. Thus, NIDDM in the rat is polygenic. The 3 NIDDM loci were found to have distinct physiologic effects. One affected postprandial but not fasting hyperglycemia, whereas the other 2 affected both. Gauguier et al. (1996) mapped up to 6 independently segregating loci predisposing to hyperglycemia, glucose intolerance, or altered insulin secretion in the GK rat. Both Galli et al. (1996) and Gauguier et al. (1996) identified a locus implicated in body weight. The close similarity between diabetes-related phenotypes in the GK rat and human NIDDM suggested to the authors that similar patterns of genetic heterogeneity may underlie the disease in humans and that the results in rats may be useful in understanding the human disease. Fakhrai-Rad et al. (2000) mapped the NIDDM1B locus in the GK rat to a 1-cM region by genetic and pathophysiologic characterization of new congenic substrains for the locus. The gene encoding insulin-degrading enzyme (IDE; 146680) was also mapped to this 1-cM region, and 2 amino acid substitutions (H18R and A890V) were identified in the GK allele which reduced insulin-degrading activity by 31% in transfected cells. However, when the H18R and A890V variants were studied separately, no effects were observed, suggesting a synergistic effect of the 2 variants on insulin degradation. No effect on insulin degradation was observed in cell lysates, suggesting that the effect may be coupled to receptor-mediated internalization of insulin. Congenic rats with the IDE GK allele displayed postprandial hyperglycemia, reduced lipogenesis in fat cells, blunted insulin-stimulated glucose transmembrane uptake, and reduced insulin degradation in isolated muscle. Analysis of additional rat strains demonstrated that the dysfunctional IDE allele was unique to GK rats. The authors concluded that IDE plays an important role in the diabetic phenotype in GK rats. Bruning et al. (1997) created a polygenic (or at least digenic) model of NIDDM in mice. The model reproduced the characteristics of the human disease, namely insulin resistance in muscle, fat, and liver, followed by failure of pancreatic beta-cells to compensate adequately for this resistance despite increased insulin secretion. Mice doubly heterozygous for null alleles in the insulin receptor (147670) and insulin receptor substrate-1 (IRS1; 147545) genes exhibited the expected reduction by approximately 50% in expression of these 2 proteins, but a synergism at the level of insulin resistance with 5- to 50-fold elevated plasma insulin levels and comparable levels of beta-cell hyperplasia. At 4 to 6 months of age, 40% of these doubly heterozygote mice became overtly diabetic. Thus, diabetes arose in an age-dependent manner from an interaction between 2 genetically determined, subclinical defects in the insulin signaling cascade, demonstrating the role of epistatic interactions in the pathogenesis of common diseases with nonmendelian genetics. Terauchi et al. (1997) likewise created a polygenic model of NIDDM by heterozygous knockout of the IRS1 gene with heterozygous knockout of the beta-cell GCK gene. They found that the genetic abnormalities, each of which was nondiabetogenic by itself, caused overt diabetes if they coexisted. The Zucker diabetic fatty (ZDF) rat is another animal model of human adipogenic NIDDM. Shimabukuro et al. (1998) demonstrated in islets of obese ZDF rats a pathway of lipotoxicity leading to diabetes. Elevated levels of circulating free fatty acids (Lee et al., 1994) and lipoproteins transport to islets of obese ZDF rats far more free fatty acids than can be oxidized. Because fa/fa islets exhibit a markedly increased lipogenic capacity and a decreased oxidative capacity, unused free fatty acids in islets are esterified and over time an excessive quantity is deposited (Lee et al., 1997). This is associated with an increase in ceramide, inducible NOS expression, and NO production, which causes apoptosis. That troglitazone, an agent that reduces islet fat in ZDF rats (Shimabukuro et al., 1997) and prevents their diabetes (Sreenan et al., 1996), is equally efficacious in human NIDDM suggests a comparable pathway of lipotoxicity to diabetes in humans. Hart et al. (2000) showed that FGF receptors 1 and 2 (136350, 176943), together with ligands FGF1 (131220), FGF2 (134920), FGF4 (164980), FGF5 (165190), FGF7 (148180), and FGF10 (602115), are expressed in adult mouse beta cells, indicating that FGF signaling may have a role in differentiated beta cells. When Hart et al. (2000) perturbed signaling by expressing dominant-negative forms of the receptors, FGFR1C and FGFR2B, in the pancreas, they found that mice with attenuated FGFR1C signaling, but not those with reduced FGFR2B signaling, developed diabetes with age and exhibited a decreased number of beta cells, impaired expression of glucose transporter 2 (138160), and increased proinsulin content in beta cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type II diabetes. Mutations in the homeobox gene IPF1/PDX1 (600733) are linked to diabetes in both mouse and human. Hart et al. (2000) showed that IPF1/PDX1 is required for the expression of FGFR1 signaling components in beta cells, indicating that IPF1/PDX1 acts upstream of FGFR1 signaling in beta cells to maintain proper glucose sensing, insulin processing, and glucose homeostasis. Yuan et al. (2001) demonstrated that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of IKBKB (603258) attenuated insulin signaling in cultured cells, whereas IKKB inhibition reversed insulin resistance. Thus, Yuan et al. (2001) concluded that IKKB, rather than the cyclooxygenases (see 600262), appears to be the relevant molecular target. Heterozygous deletion (IKKB +/-) protected against the development of insulin resistance during high fat feeding and in obese Lep (ob/ob) (see 164160) mice. Yuan et al. (2001) concluded that their findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus and identified the IKKB pathway as a target for insulin sensitization. Scheuner et al. (2005) studied glucose homeostasis in mice with a ser51-to-ala substitution at the phosphorylation site of the translation initiation factor eIF2-alpha (see 603907) and observed that heterozygous mutant mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distention of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. Scheuner et al. (2005) proposed that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type II diabetes. In Hmga1 (600701)-deficient mice, Foti et al. (2005) observed decreased insulin receptor expression in muscle, fat, and liver, largely impaired insulin signaling, and severely reduced insulin secretion, causing a phenotype characteristic of human type II diabetes. Matsuzaka et al. (2007) reported that Elovl6 (611546) -/- mice developed obesity and hepatosteatosis when fed a high-fat diet or when mated to leptin-deficient (ob/ob) mice, but showed marked protection from hyperinsulinemia, hyperglycemia, and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 (IRS2; 600797) and suppression of hepatic protein kinase C-epsilon (PRKCE; 176975), resulting in restoration of Akt (see 164730) phosphorylation. Matsuzaka et al. (2007) noted that the Elovl6 -/- mice were unique in that their insulin resistance was reduced without the amelioration of obesity or hepatosteatosis, and concluded that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. ► ▼ OVARIAN CANCER, SUSCEPTIBILITY TO, 1; OVCAS1 607893 only shown in mice For a general discussion of ovarian cancer, see 167000. MAPPING Sekine et al. (2001) performed genomewide linkage analysis in 58 Japanese patients and 9 unaffected members among 28 familial ovarian cancer families with no mutation in BRCA1 (113705) or BRCA2 (600185). Mean age at diagnosis was 49.7 years. Chromosome 3p25-p22 showed a suggestive score for linkage (lod = 3.49 and NPL = 2.77 at D3S3611) based on a multipoint analysis. Additionally, based on a 2-point analysis using dense markers, this 3p25-p22 region showed a P value of less than 0.05 at 10 markers and suggestive evidence for linkage at 2 markers within 19 cM (NPL = 2.60 and 2.49 at D3S1597 and D3S3611, respectively). The frequency of loss of heterozygosity at 4 markers in this region was greater than 50% only in tumor tissues from patients with no mutation in BRCA1 or BRCA2, not in those with a BRCA1 mutation. The authors proposed that a novel tumor suppressor gene may be located in this region of chromosome 3. ► ▼ PROSTATE CANCER, HEREDITARY, 12; HPC12 611868 only shown in mice A number sign (#) is used with this entry because single-nucleotide polymorphism (SNP) in the EHBP1 gene (609922) is associated with the development of prostate cancer. For a general discussion of hereditary prostate cancer, see 176807. Gudmundsson et al. (2008) conducted a genomewide single-nucleotide polymorphism (SNP) association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. They identified a novel variant that was associated with prostate cancer: the A allele of dbSNP rs721048 on 2p15 (odds ratios (OR) = 1.15, P = 7.7 x 10(-9)). The SNP dbSNP rs721048 is located within one of the introns of the EHBP1 gene, which has been implicated in endocytic trafficking. RT-PCR analysis detected expression of EHBP1 in several different tissue libraries, including those derived from the prostate. The dbSNP rs721048 A allele showed a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease. ► ▼ PROSTATE CANCER, HEREDITARY, 4 608658 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Because Americans of Ashkenazi Jewish descent comprise a population with a relatively limited number of founders, Friedrichsen et al. (2004) hypothesized that genomewide linkage analyses of hereditary prostate cancer families in this population would increase locus homogeneity and the likelihood of finding a true susceptibility locus. They therefore performed a genomewide scan of 36 Jewish families: 17 from the Fred Hutchinson Cancer Research Center and 19 families collected by The Johns Hopkins University. The data highlighted the 7q11-q21 region, with a nonparametric linkage (NPL) score of 3.01. After genotyping additional markers within the 7q11-q21 peak, the NPL score increased to 3.35. In a large 2-stage genomewide association study of prostate cancer involving white participants from the United Kingdom and Australia screening 541,129 SNPs, Eeles et al. (2008) found association of a single-nucleotide polymorphism (SNP) in intron 9 of the LMTK2 gene, dbSNP rs6465657, and susceptibility to prostate cancer (P = 1.1 x 10(-9)). The LMTK2 gene maps to chromosome 7q21-q22. ► ▼ PROSTATE CANCER, HEREDITARY, 11; HPC11 611955 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. MAPPING Gudmundsson et al. (2007) performed a genomewide association scan of 1,501 Icelandic men with prostate cancer and 11,290 controls, followed by 3 case-control replication studies in individuals from the Netherlands, Spain, and Chicago and found an association between prostate cancer and the A allele of dbSNP rs4430796 in intron 2 of the TCF2 gene (HNF1B; 189907) (p = 1.4 x 10(-11) for the combined studies). The authors noted that the risk conferred by this variant is modest (allele odds ratio, 1.22), but because it is common, the population-attributable risk is substantial. In a large genomewide association study of prostate cancer, Thomas et al. (2008) confirmed the association found by Gudmundsson et al. (2007) with the A allele of the SNP dbSNP rs4430796 (9.58 x 10(-10)). In a large 2-stage genomewide association study of prostate cancer involving white participants from the United Kingdom and Australia screening 541,129 SNPs, Eeles et al. (2008) found 6 strongly associated SNPs on chromosome 17 (P less than 10(-6)). Four of these were at 17q12, with the strongest association observed for dbSNP rs7501939 in the HNF1B gene (OR = 0.71, P = 10(-12)). A P value of 8.3 x 10(-12) was observed for the SNP dbSNP rs4430796. Sun et al. (2008) carried out a fine mapping study of the HNF1B gene at 17q12 in 2 study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (dbSNP rs4430796); these loci are separated by a recombination hotspot. Sun et al. (2008) confirmed the association with a SNP in the second locus (dbSNP rs11649743) in 5 additional populations, with P = 1.7 x 10(-9) for an allelic test of the 7 studies combined. The association at each SNP remained significant after adjustment for the other. By targeted SNP analysis of 542 non-Hispanic men with prostate cancer from 403 families and 473 unaffected men, Levin et al. (2008) found that the A allele of dbSNP rs4430796 in the HNF1B gene on 17q12 was significantly associated with prostate cancer, particularly among men diagnosed before age 50 years (p = 0.006 with an odds ratio of 1.92), but not later age (p = 0.118). Homozygous carriers of the A allele had a 3.70-fold increased risk of developing prostate cancer at an early age compared to noncarriers. The results confirmed the prostate cancer association with SNPs on chromosome 17q12, and indicated that this locus may also play a role in hereditary prostate cancer with early onset. ► ▼ PROSTATE CANCER, HEREDITARY, 5; HPC5 609299 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Rokman et al. (2005) performed linkage analysis using 17 fine-mapping markers in 16 multiplex Finnish families with hereditary prostate cancer and found evidence for linkage at 3p26, with a multipoint heterogeneity adjusted lod of 3.39. The highest lod scores were around markers D3S1270 and D3S4559 (alpha = 0.89), narrowing the peak region to approximately 2 cM. Rokman et al. (2005) concluded that 3p26 is likely to contain a predisposing gene for Finnish hereditary prostate cancer, although no disease-segregating variants were found in 2 candidate genes in the region. ► ▼ RENAL CELL CARCINOMA, Xp11-ASSOCIATED; RCCX1 300854 only shown in mice no details in our DB, please see OMIM ► ▼ PROSTATE CANCER, HEREDITARY, 3 608656 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Berry et al. (2000) found evidence for a prostate cancer susceptibility locus on 20q13, which they called HPC20, particularly in families having fewer than 5 affected members (multipoint nonparametric linkage score (NPL) 3.22, P = 0.00079), a later average age of diagnosis (multipoint NPL 3.40, P = 0.0006), and no male-to-male transmission (multipoint NPL 3.94, P = 0.00007). The group of 19 patients having all 3 of these characteristics had a multipoint NPL of 3.69 (P = 0.0001). To further assess the potential contribution of a 20q13 locus to prostate cancer susceptibility, Bock et al. (2001) studied 172 unrelated families affected by prostate cancer, using 17 polymorphic markers across a 98.5-cM segment of chromosome 20 that contains the candidate region. The strongest evidence for linkage was seen in a subset of 16 black families (lod 0.86), but in general the linkage study did not provide statistically significant support for the existence of a prostate cancer-susceptibility locus at 20q13. Zheng et al. (2001) found elevated NPL scores in a study of 159 hereditary prostate cancer families and higher NPL scores in subsets of families with a later age of diagnosis (65 years or later; NPL 1.94), fewer than 5 affected family members (NPL 1.74), or no male-to-male disease transmission (NPL 1.01). The region with positive linkage scores spanned approximately 60 cM from 20pter to 20q11 in these subsets of families. ► ▼ TYPE 2 DIABETES MELLITUS 3; T2D3 603694 only shown in mice Ghosh et al. (1999) conducted a genome scan at an average resolution of 10 cM for type II diabetes (125853) susceptibility genes in 716 affected sib pairs from 477 Finnish families. At the time of report, their best evidence for linkage was on chromosome 20, with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum lod (MLS) was 3.08 on 20p under an additive model, whereas the weighted MLS was 2.06 on 20q. They interpreted the evidence from this and other studies as suggesting at least 2 diabetes-susceptibility genes located on chromosome 20. Ghosh et al. (1999) also screened the HNF4A gene (600281), which is responsible for type I maturity-onset diabetes of the young (125850), in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. They found no evidence that sequence changes in the HNF4A gene accounted for the linkage results they observed. Linkage to a 20-cM region of 20q12-q13.1 was found by Bowden et al. (1997), Ji et al. (1997), and Zouali et al. (1997). Since few mutations were found in the HNF4A gene, which is mutant in MODY1 (125850), one or more other genes within 20q12-q13.1 were thought to be responsible for the observed genetic linkage to type II diabetes. Price et al. (1999) constructed a radiation hybrid map and YAC/BAC physical map for precise mapping of newly identified transcribed sequences and polymorphic markers. They suggested that this map would aid in linkage and linkage disequilibrium studies and facilitate identification and cloning of candidate type II diabetes susceptibility genes in this region of the genome. Familial genetic studies of noninsulin-dependent diabetes mellitus (NIDDM; 125853) of different human populations, including French Caucasians, suggested evidence for linkage of NIDDM and chromosome 20q13, where the MC3R gene maps. Hani et al. (2001) assessed the MC3R gene for variations in a large cohort of French families with NIDDM. In these patients they identified 2 missense mutations in the MC3R gene. These 2 variants, which were in complete linkage disequilibrium, were also present in nondiabetic controls. Based on association and familial linkage disequilibrium test results, the authors stated that these MC3R gene-coding variants were not associated with diabetes or obesity. They concluded that these variants were marginally associated with insulin and glucose levels during oral glucose tolerance testing in normoglycemic subjects. ► ▼ TYPE 2 DIABETES MELLITUS 1; T2D1 601283 only shown in mice A number sign (#) is used with this entry because of the possibility that, in some cases, susceptibility to noninsulin-dependent diabetes mellitus (NIDDM1) is caused by mutation in the CAPN10 gene (605286). For a phenotypic description and a discussion of genetic heterogeneity of noninsulin-dependent diabetes mellitus, see 125853. Hanis et al. (1996) performed a genomewide search that revealed a major susceptibility locus for NIDDM on chromosome 2. The study was performed on 330 affected sib pairs from Mexican American families living close to the Rio Grande River in Texas. Marker D2S125, which is located in the distal part of the long arm of chromosome 2 (2q37), showed significant evidence of linkage to NIDDM and appeared to be a major factor affecting the development of diabetes mellitus in Mexican Americans. Hanis et al. (1996) proposed that the locus be designated NIDDM1. Using linkage analysis in a Finnish sample comprising 709 affected sib pairs from 472 sibships, Ghosh et al. (1998) excluded linkage to 2q37. They discussed possible reasons why linkage was not found and concluded that this region is unlikely to play a major role in NIDDM susceptibility in the Finnish Caucasian population. Genetic analyses of complex disorders such as diabetes, cardiovascular disease, asthma, hypertension, and psychiatric illnesses, when they allow for the simultaneous consideration of susceptibility from multiple chromosomal regions, may improve the ability to map the responsible genes. Cox et al. (1999) described an approach to assessing the evidence for statistical interactions between unlinked genome regions that allows multipoint allele-sharing analysis to take the evidence for linkage at one region into account in assessing the evidence for linkage over the rest of the genome. Using this method, they showed that the interaction of genes on chromosome 2 (NIDDM1) and chromosome 15 (near CYP19 (107910), which maps at 15q21.1) makes a contribution to susceptibility to type II diabetes in Mexican Americans from Starr County, Texas. Horikawa et al. (2000) identified the CAPN10 gene in a 66-kb region in chromosome band 2q37.3, within the NIDDM1 region. Altshuler et al. (2000) described the statistical test developed by Horikawa et al. (2000), termed 'partitioning of linkage,' which demands association of an allele not just with disease but with those cases 'linked' to the locus under investigation. By applying this test, Horikawa et al. (2000) found that a SNP in intron 3 of the CAPN10 gene, designated SNP43 (605286.0001), showed a statistically significant increase in the frequency of the common G allele in patients and in addition was associated with evidence for linkage. Horikawa et al. (2000) identified 3 polymorphisms in the CAPN10 gene (SNP43; SNP19, 605286.0002; SNP63, 605286.0003) that were used to define a high-risk 112/121 haplotype combination for development of type II diabetes in Mexican American, Finnish, and German populations. Cox (2001) reviewed the evidence for implicating CAPN10 as a susceptibility gene for NIDDM1. Busfield et al. (2002) studied indigenous Australian populations which, like some other populations including Mexican Americans, have an extraordinarily high frequency of type II diabetes consistent with the hypothesis of the 'thrifty genotype.' In a large multigeneration pedigree segregating NIDDM in a single community, they found a maximum 2-point lod score of 2.97 at marker D2S2345, and a multipoint peak lod score of 3.9 for a location less than 1 cM from D2S2345. In a population-based study of 454 Korean patients with type II diabetes, Kang et al. (2006) found a significant association with the 111/121 CAPN10 diplotype (odds ratio of 2.58). The high-risk 112/121 diplotype for type II diabetes identified in Mexican Americans was not significant in the Korean population. ► ▼ PROSTATE CANCER, HEREDITARY, 8; HPC8 602759 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Berthon et al. (1998) performed a linkage study using a set of European families (French and German) with 3 or more prostate cancer patients per family. They concluded that there is a prostate cancer susceptibility locus on 1q42.2-q43, significantly distant from HPC1 (601518) on 1q24-q25 (Smith et al., 1996). The primary localization was confirmed with several markers by use of 3 different genetic models. They obtained a maximum 2-point lod score of 2.7 with marker D1S2785. Multipoint parametric and nonparametric linkage (NPL) analysis yielded maximum hlod and NPL scores of 2.2 and 3.1, respectively, with an associated P value of 0.001. Homogeneity analysis with multipoint lod scores gave an estimate of the proportion of families with linkage to the 1q42.2-q43 locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, 9 of the 47 families with early-onset prostate cancer (at an age less than 60 years) gave multipoint lod and NPL scores of 3.31 and 3.32, respectively, with P = 0.001. Gibbs et al. (1999) analyzed 152 families with prostate cancer for linkage to markers spanning a 20-cM region of 1q42.2-q43. No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in the total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, the pedigrees were stratified into more homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although lod scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least 5 affected men. If heterogeneity is assumed, an estimated 4 to 9% of these 152 families may show linkage in this region. Cancel-Tassin et al. (2001) examined evidence for linkage to the PCAP locus in 64 (37 previously reported French, 24 newly identified French, 2 Spanish and 1 Italian) families with an average number of affected individuals of 3.75 and an average age at diagnosis of 66.4 years. Using both parametric and nonparametric linkage methods, results in favor of linkage were observed with a maximum multipoint NPL score of 2.86 at D1S2785 and a maximum hlod score of 2.65 between markers D1S321 and D1S2842. Homogeneity analysis indicated that up to 50% of the families were linked to this locus. A subset of 25 families with mean age at diagnosis under 66 years of age contributed significantly to the evidence of linkage with a maximum multipoint NPL score of 2.03 at D1S2842. These results suggested that PCAP is the most frequent known locus predisposing to hereditary prostate cancer in southern and western Europe. ► ▼ PROSTATE CANCER, HEREDITARY, 1; HPC1 601518 only shown in mice Oncology: Prostate cancer Inheritance: Autosomal dominant form A number sign (#) is used with this entry because of evidence that the form of hereditary prostate cancer, HPC1, that maps to 1q24-q25 is caused by germline mutations in the gene encoding ribonuclease L (RNASEL; 180435). For a general discussion of hereditary prostate cancer, see 176807. Smith et al. (1996) noted that segregation analysis of familial prostate cancer suggests the existence of at least 1 dominant susceptibility locus and predicts that high-risk alleles at such loci account in the aggregate for 9% of all prostate cancers and for more than 40% of early-onset disease. They stated further that prostate cancer presents a number of serious obstacles to linkage analysis, including occurrence of phenocopies, late age of onset, and absence of clinical features that might allow subgrouping to reflect potential genetic heterogeneity. Smith et al. (1996) undertook linkage analysis in 79 North American and 12 Swedish pedigrees, each having at least 3 first-degree relatives with prostate cancer. In these families there was also evidence of bilineal inheritance. Affected individuals had an average age at diagnosis of 65 years, with a total of 34 men diagnosed before the age of 55. The investigators analyzed a total of 341 dinucleotide repeat markers in a subgroup of 66 North American families. For the parametric analysis of the data they used a model of dominant inheritance that included a fixed phenocopy rate of 15% and the assumption that unaffected men over 75 were not likely to be gene carriers. The highest lod score observed was 2.75 with the marker D1S218, which maps to the distal long arm of chromosome 1 at 1q24-q25. The investigators then typed additional markers in this region in all 79 North American families and the 12 Swedish families. This analysis provided additional evidence for linkage with a maximum 2-point lod score of 3.65 at theta = 0.18 with marker D1S2883. Significant evidence for locus heterogeneity was obtained by an admixture test, which estimated that 34% of families were linked to the 1q24-q25 region. The maximum multipoint lod score with markers D1S2883, D1S158, and D1S422 under the assumption of heterogeneity was 5.43, with the postulated susceptibility locus mapping close to D1S422. Smith et al. (1996) found no clinical features that appeared to distinguish families showing linkage to chromosome 1 from unlinked families. They noted that Cher et al. (1996) reported that a large portion of chromosome 1, including 1q24-q25, is frequently increased in copy number in advanced prostate cancer specimens examined by comparative genomic hybridization. Smith et al. (1996) proposed the designation of HPC1 (hereditary prostate cancer 1) for the locus. They emphasized that early diagnosis can be life-saving in prostate cancer and that the potential ability to identify individuals at high genetic risk, when combined with physical exam, transrectal ultrasound, and prostate-specific antigen (176820) analysis, could ultimately be of significant medical benefit. McIndoe et al. (1997) reported results of linkage analysis in the region of the putative HPC1 locus on 1q24-q25. The study was part of the Prostate Cancer Genetic Research Study (PROGRESS) at the Fred Hutchinson Cancer Research Center in Seattle. Analysis by 2 parametric methods and 1 nonparametric method failed to confirm linkage to this region. Additionally, they were unable to demonstrate heterogeneity within the dataset. Cooney et al. (1997) confirmed 1q24-q25 as a likely location of a prostate cancer susceptibility gene. Nonparametric multipoint linkage analysis of data on 6 polymorphic marker sequences covering the candidate chromosomal region were performed in 59 unrelated families selected for analysis on the sole criterion that more than 1 living family member was affected by prostate cancer. In the entire set of 59 families, tight linkage to D1S466 was found; maximum lod = 1.58. In 20 families fulfilling more rigorous criteria, i.e., 3 or more affected individuals within one nuclear family, affected individuals in 3 successive generations, and/or clustering of 2 or more individuals affected before the age of 55 years a maximum lod score of 1.72 was observed with the same marker. The 6 African American families in this study contributed disproportionately to the observation of linkage, with a maximum nonparametric linkage (NPL) Z score at marker D1S158 of 1.39. Using both parametric and nonparametric methods, Eeles et al. (1998) attempted to confirm the assignment of a locus (HPC1) to 1q in a study of 60 affected related pairs and 76 families with 3 or more cases of prostate cancer, but could find no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. They concluded that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least 4 cases of the disease. The original study of Smith et al. (1996) mapping the HPC1 gene to 1q24-q25 involved 91 North American and Swedish families, each with multiple cases of prostate cancer. Gronberg et al. (1999) analyzed 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer that, on the basis of 40 markers spanning a 25-cM interval within 1q24-q25, showed evidence of linkage. In the complete set of families, a maximum 2-point lod score of 1.10 was observed at D1S413 (at a recombination fraction of 0.1), with a maximum NPL Z score of 1.64 at D1S202 (P = 0.5). The evidence for linkage to this region originated almost exclusively from a subset of 12 early-onset (age less than 65 years) families, which yielded a maximum lod score of 2.38 at D1S413 (theta = 0.0) and an NPL Z score of 1.95 at D1S422 (P = 0.3). Estimates from heterogeneity tests suggested that, within Sweden, as many as 50% of early-onset families have linkage to the HPC1 region. Neuhausen et al. (1999) examined evidence for linkage to the 1q24-q25 region in a set of 41 extended multicase prostate cancer pedigrees from Utah containing 440 members with prostate cancer. In comparison with the families reported in the initial localization by Smith et al. (1996), the Utah pedigrees were generally much larger (average of 10.7 vs 5.1 cases) and had an older average age at diagnosis (69 vs 65 years). The authors found that the youngest quartile (by median age at diagnosis) yielded a maximum lod of 2.82, P = 0.0003 (at D1S215 to D1S222), compared with a maximum lod of 0.73, P = 0.07 for the oldest quartile pedigrees at the same locus. In a combined analysis for 6 markers in the 1q24-q25 region in 772 families segregating hereditary prostate cancer, Xu and the International Consortium for Prostate Cancer Genetics (2000) found some evidence for linkage with a peak parametric multipoint lod score assuming heterogeneity (hlod) of 1.4 (p = 0.01) at D1S212. In a subset of 491 families with male-to-male disease transmission, the hlod score was 2.56 (p = 0.0006) whereas the score was zero in the remaining 281 families. The authors stated that the results supported the finding of a prostate cancer susceptibility gene linked to 1q24-q25 in a defined subset of families in which several members are affected at an early age and in which there is male-to-male transmission. Cancel-Tassin et al. (2001) examined evidence for linkage to the HPC1 locus in 64 (37 previously reported and 27 newly identified) families from southern and western Europe with at least 3 affected individuals with prostate cancer and an average age at diagnosis of 66.4 years. Using both parametric and nonparametric linkage methods, no significant evidence of linkage was observed. A subset of 25 families with earlier age of diagnosis (under 66 years) also showed negative lod scores. Under the assumption of heterogeneity, low positive lod scores were obtained in a small proportion of families. By a positional cloning/candidate gene method, Carpten et al. (2002) identified the ribonuclease L gene (180435) as the site of germline mutations in 2 HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway, and it had been a suggested tumor suppressor gene. In that connection, Carpten et al. (2002) found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozygous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway may provide opportunities for developing therapies for those with prostate cancer. ► ▼ RHEUMATOID ARTHRITIS; RA 180300 only shown in mice Joints: Rheumatoid arthritis Immunology: HLA-DRB1 association Limbs: Rheumatoid nodules Pulm: Rheumatoid lung disease Vascular: Rheumatoid vasculitis Heme: Felty syndrome Neuro: Rheumatoid vasculitic mononeuritis Inheritance: Unproved inheritance A number sign (#) is used with this entry because multiple factors, including HLA type (see HLA-DRB1; 142857), influence the susceptibility to rheumatoid arthritis. Evidence suggests that several polymorphisms in various genes may also be associated with susceptibility to rheumatoid arthritis, including SLC22A4 (604190.0001), PTPN8 (600716.0001) MHC2TA (600005.0007), IRF5 (607218.0002), and NFKBIL1 (601022.0001). See also MOLECULAR GENETICS below. DESCRIPTION Rheumatoid arthritis is an inflammatory disease, primarily of the joints, with autoimmune features and a complex genetic component. INHERITANCE Occasional families show a considerable number of cases of this common disorder. A simple mendelian mechanism could not be proved, however. Indeed, some (Burch et al., 1964) could not demonstrate significant familial aggregation. Lynn et al. (1995) conducted family studies and segregation analyses of RA based on consecutive patients with RA ascertained without regard to family history or known risk factors. Included in the analyses were first-degree relatives from 135 simplex and 30 multiplex families. A highly penetrant recessive major gene, with a mutant allele frequency of 0.005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. Although both proband gender and age at onset were identified as important risk factors, proband gender appeared to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. For future genetic analyses, Lynn et al. (1995) suggested that families with an excess of affected males having a young age at onset might be most informative in identifying the putative recessive gene and its modifiers. Hasstedt et al. (1994) studied 28 pedigrees ascertained through pairs of first-degree relatives with RA. RA was confirmed in 77 pedigree members, including probands; the absence of disease was verified in an additional 261 pedigree members. Members of the pedigrees were typed serologically for HLA. Analyses supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 0.0216, and estimated the lifetime penetrance as 41% in male homozygotes and 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variants with HLA genotypes to genetic or environmental effects shared by sibs. The genetic model inferred in this analysis was considered consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounted for approximately one-half of familial RA, although it accounted for only approximately one-fifth of the RA in the population. PATHOGENESIS Upregulation of proinflammatory cytokines in RA synovium and synovial fluid is a feature of active disease and intense inflammation. Antiinflammatory mediators are also present and activated in RA but fail to counterregulate the proinflammatory cytokines. Muller-Ladner et al. (2000) found that the IL4-STAT (STAT6; 601512) pathway is activated in patients with short-term (less than 1 year) and long-term (more than 2 years) RA and may contribute to downregulation of the immunologic activity in RA synovium. In a T-cell receptor transgenic mouse model, an inflammatory arthritis that resembles human RA is initiated by T cells but is sustained by antibodies to GPI (172400). Using ELISA analysis, Schaller et al. (2001) detected high levels of antibody to GPI, independent of the presence of rheumatoid factor, in serum and synovial fluid of most RA patients; antibodies to GPI were rare in controls or in patients with Lyme arthritis or Sjogren syndrome. In addition, the authors found high levels of GPI in sera and synovial fluid and the presence of GPI-containing immune complexes in RA synovial fluid. Immunohistochemical analysis and confocal microscopy demonstrated intense expression of GPI on the surface of endothelial cells of synovial arterioles and some capillaries, but not venules or in other tissues. Intense patchy expression was observed on the surface lining of hypertrophic synovium, particularly where the hypertrophic villus formed; this expression pattern resembled that for vascular permeability factor (VEGF/VPF; 192240). Schaller et al. (2001) suggested that GPI may be presented to the immune system either on endothelial cell surfaces or as a soluble protein in synovial fluid of inflamed RA joints, leading to antibody binding or to immune complex formation with complement activation, respectively. In either case, they concluded that there is a role for autoantibody in the pathology of RA and that there may be scope for antibody treatments for the disease. Using a rheumatoid factor (RF+) transgenic B cell hybridoma line originally isolated from an autoimmune MRL/lpr mouse used as a model for SLE, Leadbetter et al. (2002) determined that these cells respond only to IgG2a immune complexes containing DNA and not to haptens or proteins. After ruling out complement receptors (i.e., CD21/CR2, 120650) as a potential second receptor on B cells, screening of cells expressing the adaptor protein Myd88 (602170), through which all toll-like receptors signal, revealed that RF+ B cells lacking Myd88 are completely unresponsive to IgG2a antinucleosome monoclonal antibodies (mAb). TLR9 (605474) responsiveness to CpG oligodeoxynucleotides (ODN) is presumed to require endosome acidification. The response to stimulation of RF+ B cells by IgG2a mAb or CpG-ODN, but not by TLR2 (603028) or TLR4 (603030) agonists, was blocked by inhibitors of endosome acidification, notably chloroquine, suggesting a mechanistic basis for its efficacy in the treatment for both RA and SLE. Leadbetter et al. (2002) proposed that other endogenous subcellular nucleic acid-protein autoantigens may signal through other TLRs to abrogate peripheral B-cell tolerance. They also suggested that infectious agent PAMP (patterns associated with microbial pathogens) engaging TLRs may create a synergy with autoantibody-autoantigen immune complexes, thus explaining the association between infection and autoimmune disease flares. Nedvetzki et al. (2003) identified a CD44 variant (107269), designated CD44vRA, in synovial fluid aspirated from 23 of 30 patients with rheumatoid arthritis. Functional expression studies in human cells showed that the CD44vRA variant interacted with FGF2 (134920) via the heparan sulfate on exon v3 in a way that enhanced binding and activation of soluble FGFR1 (136350) to a greater extent than CD44v3-v10. Synovial fluid cells from RA patients bound soluble FGFR1 more intensively than control cells. Nedvetzki et al. (2003) postulated that activation of FGFR1 may play a role in the RA inflammatory process. Seyler et al. (2005) analyzed synovial tissue specimens from 72 patients with RA for TNFSF13 (604472) and TNFSF13B (603969) production and TNFSF13/TNFSF13B receptor expression. In synovitis with ectopic germinal centers present, inhibiting TNFSF13 and TNFSF13B with a TACI (TNFRSF13B; 604907):Fc fusion protein resulted in destruction of the germinal centers and marked inhibition of IFN-gamma (147570) and Ig transcription, whereas similar inhibition in the aggregate and diffuse types of synovitis enhanced IFN-gamma production and did not affect Ig levels. These differential immunomodulatory effects correlated with the presence of TACI-positive T cells in aggregate and diffuse synovitis and their absence in synovitis with germinal centers. Seyler et al. (2005) proposed that TNFSF13 and TNFSF13B regulate B-cell as well as T-cell function and have both pro- and antiinflammatory effects in RA. Boilard et al. (2010) investigated the role of platelets in rheumatoid arthritis. Boilard et al. (2010) identified platelet microparticles--submicrometer vesicles elaborated by activated platelets--in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluids from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1 (see 147760). Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, Boilard et al. (2010) identified the collagen receptor glycoprotein VI (GP6; 605546) as a key trigger for platelet microparticle generation in arthritis pathophysiology. Boilard et al. (2010) concluded that their findings demonstrated a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases. MAPPING - Linkage to HLA on Chromosome 6p21 Cornelis et al. (1998) performed a genome scan with 114 European Caucasian rheumatoid arthritis sib pairs from 97 nuclear families. Linkage was significant only for HLA and nominal for 19 markers in 14 other regions. Four of the loci implicated in IDDM potentially overlap with these regions: IDDM6 (601941), IDDM9, IDDM13 (601318), and DXS998. The first 2 of these candidate regions, defined in the rheumatoid arthritis genome scan on 18q22-q23 and 3q13, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0.001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA; HLA had previously been estimated to account for one-third of the genetic component. The candidate genes in this area included those coding for CD80 (112203) and CD86 (601020), molecules involved in antigen-specific T-cell recognition. The expressed T-cell receptor (TCR) consists of an alpha (186880) and beta (186930), or gamma (186970) and delta (186810) chain heterodimer. More than 95% of peripheral T lymphocytes expressed TCR alpha/beta chains. Nanki et al. (1996) stated that the TCR variable regions of functional alpha and beta chains are constructed by rearrangement of variable (V), diversity (D) (beta chain only), and joining (J) gene segments with additional noncoding (N) regions. The expressed TCRBV gene repertoires in peripheral blood lymphocytes are controlled genetically and primarily by HLA. The regulation of the human TCRBJ gene repertoire had been difficult to analyze because of the potentially complex number of BJ gene rearrangements. To overcome this problem, Nanki et al. (1996) developed a PCR-ELISA method to study BJ gene expression, and compared peripheral T lymphocytes from 12 pairs of monozygotic twins, including 6 rheumatoid arthritis discordant pairs, and 5 normals. Because monozygotic twins share identical genetic backgrounds, the investigators reasoned that differences in the twins' TCRBJ repertoires might be due to environmental or stochastic factors. If a systemic autoimmune disease, such as RA, was triggered by a single potent environmental stimulus, the peripheral T-lymphocyte TCRBJ repertoire might be skewed. In contrast, an antigenic peptide would not necessarily expand T cells with specific TCRBV gene products, which interact primarily with the MHC backbone. Nanki et al. (1996) was surprised to find that TCRBJ expression is controlled genetically. Even a chronic autoimmune syndrome such as RA has little influence on the overall pattern of TCRBJ expression. The BJ gene repertoires of monozygotic twins were more similar than those of unrelated individuals and the inflammation of RA did not induce specific changes in the genetically determined pattern of BJ expression. The HLA-DRB1 (142857) locus has been shown to be linked to and associated with RA susceptibility. In addition to the HLA-DRB1 locus, it was considered likely that genes with weaker effects are also involved. Cox et al. (1999) used a combined sib-TDT (transmission/disequilibrium test) and TDT, in addition to parametric and nonparametric linkage methods, to investigate candidate genes of the interleukin-1 (IL1) gene cluster (see IL1A; 147760) on 2q13, since IL1 is an important cytokine in the control of the inflammatory response central to RA pathology. Several tightly linked IL1 cluster markers yielded suggestive evidence for linkage in those families in which affected sibs did not share 2 HLA-DRB1 alleles identical by descent. The evidence was significant in those with severe disease, as assessed by the presence of bone erosions. Jawaheer et al. (2001) reported a genomewide screen of multiplex families with RA gathered in the U.S. by a consortium of investigators. Using 379 microsatellite markers, they screened for allele sharing in 257 families containing 301 affected sib pairs. The results suggested that genes in the HLA complex play a major role in RA susceptibility, but that several other regions also contribute significantly to overall genetic risk. Some of these regions had previously been implicated in other diseases of an autoimmune nature, including systemic lupus erythematosus (152700), inflammatory bowel disease (266600), multiple sclerosis (126200), and ankylosing spondylitis (106300). Using 54 markers distributed across the entire HLA complex, Jawaheer et al. (2002) performed an extensive haplotype analysis in a set of 469 multiplex families with RA. The results showed that, in addition to associations with the DRB1 alleles, at least 2 additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral Al-B8-DRB103 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB10404 haplotypes. The data emphasized the importance of defining haplotypes when trying to understand HLA associations with disease, and clearly demonstrated that such associations with RA are complex and cannot be completely explained by the DRB1 locus. In a set of Japanese patients with RA and a control group, Ota et al. (2001) identified a second HLA-DRB1-independent RA susceptibility locus at the telomeric end of the HLA class III region, almost 1 Mb away from HLA-DRB1. Zanelli et al. (2001) and Jawaheer et al. (2002) likewise reported findings indicating the existence of a second RA susceptibility locus at the telomeric end of the HLA region. Using microsatellites, Ota et al. (2001) narrowed the second RA susceptibility region to 70 kb telomeric of the TNFA gene (191160). John et al. (2004) compared the utility of single-nucleotide polymorphisms (SNPs) with that of microsatellites for linkage analysis in a whole-genome screen of 157 families with multiple cases of RA. The SNP analysis detected HLADRB1, the major RA susceptibility locus (P = 0.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, 4 loci were detected at a nominal significance level (P less than 0.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. Thus, they demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allowed loci to be defined more precisely. - Associations Pending Confirmation In a metaanalysis of 4 major RA genomewide linkage studies, Fisher et al. (2003) found that, in addition to the HLA locus (p less than 0.00002), the strongest evidence for an RA susceptibility locus was on chromosome 16 (p = 0.004), a locus that had not been identified as statistically significant in any of the 4 individual RA genome searches. In total, 12 regions achieved a significant (p less than 0.05) summed rank, and 4 of these regions (on chromosomes 6p, 6q, 12p, and 16cen) reached a significance value of p less than 0.01. Amos et al. (2006) performed a genomewide linkage scan using more than 5,700 informative SNPs in 642 Caucasian families containing 1,371 affected sib pairs with rheumatoid arthritis and found nearly significant linkage at chromosome 2q33 (lod score, 3.52). A suggestive locus was identified at chromosome 11p12 (lod score, 3.09). The median age at onset in this patient population was 39 years. Using numerous SNPs and insertion/deletion polymorphisms of 4 genes located in the 70-kb region on chromosome 6 identified by Ota et al. (2001) as harboring a second RA susceptibility locus, Okamoto et al. (2003) identified the locus as the T allele at position -62 of the T/A SNP in the promoter region of the NFKBIL1 gene (601022.0001) on chromosome 6p21. The T allele (-62T) is a putative binding site for the transcription factor delta-EF1 (TCF8; 189909) (Allcock et al., 2001). In contrast, the nonsusceptible allele (-62A) is likely to disrupt this motif for delta-EF1. In a genomewide association study involving 2 large groups of case subjects with autoantibodies against cyclic citrullinated peptide (CCP) Plenge et al. (2007) identified a SNP on chromosome 9, dbSNP rs3761847, that showed association with rheumatoid arthritis for all samples tested (OR = 1.32, 95% confidence interval, 1.23 to 1.42; P = 4 x 10(-14)). This SNP showed the strongest association among several in a 100-kb region containing the TRAF1 (601711) and C5 (120900) genes. No coding SNP was found that could explain the association. In a genomewide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America, Gregersen et al. (2009) found an association with a SNP dbSNP rs13031237 in the REL (164910) gene on chromosome 2p13 (p = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed the association for dbSNP rs13031237 (odds ratio of 1.25; p = 3.08 x 10(-14)). Using the combined dataset, the authors found an allelic odds ratio of 1.21 (p = 2.60 x 10(-11)) for dbSNP rs13017599. The combined dataset also provided support for associations at both CTLA4 (123890) on chromosome 2q33 (dbSNP rs231735; OR = 0.85; p = 6.25 x 10(-9)) and BLK (191305) on chromosome 8p23 (dbSNP rs2736340; p = 5.69 x 10(-9)). MOLECULAR GENETICS Patients with vascular complications of RA have an expansion of CD4 (186940)-positive/CD28 (186760)-null T cells that may be involved in endothelial cell damage. By flow cytometric and RT-PCR analyses, Yen et al. (2001) showed that CD4-positive/CD28-null T-cell clones from RA vasculitis patients frequently expressed the stimulatory receptor KIR2DS2 (604953) in the absence of inhibitory receptors such as KIR2DL2 (604937) or KIR2DL3 (604938). Yen et al. (2001) noted that KIR genes are variably present in the Caucasian population, with the majority positive for inhibitory KIR. Comparable numbers of normal individuals and RA patients could be typed for either KIR2DS1 (604952) or KIR2DS2, whereas patients with unequivocal vasculitis had a highly significant association with KIR2DS2, suggesting that KIR2DS2 affects not the risk of developing RA but rather the risk of developing vascular complications. HLA-C polymorphisms (142840) are recognized by KIR2DS family proteins. HLA-C genotyping revealed that all RA patients had a decreased frequency of HLA-C04 and an increased frequency of HLA-C05, but RA vasculitis patients had a frequency of HLA-C03 nearly double that of normal individuals and much higher than that of other RA patients. Logistic regression analysis determined that both HLA-C03 and KIR2DS2 are independent, significant risk factors for RA vasculitis. Yen et al. (2001) concluded that MHC class I-recognizing receptors are implicated in the pathogenesis of RA vasculitis and possibly of other acute and chronic diseases characterized by vascular inflammation. Vandenbroeck et al. (2003) typed 4 microsatellite markers, located in a 118-kb interval that contains both the interferon-gamma (IFNG; 147570) and interleukin-26 (IL26; 605679) genes on chromosome 12q15, in 251 patients with RA and 198 controls. Marker D12S2510, which is located 3 kb 3-prime from the IL26 gene, was significantly associated with RA in women (p = 0.008) but not in men. A 3-marker haplotype, IFNGCA13;D12S25108;D12S25119, was inferred that showed significant underrepresentation in women but not men with RA. Vandenbroeck et al. (2003) concluded that common polymorphisms in the IFNG/IL26 gene region may contribute to sex bias in susceptibility to RA. Lard et al. (2003) compared allele frequencies of the promoter -2849A/G polymorphism of the IL10 gene (124092.0002) in 283 patients with RA, 413 patients with other rheumatic diseases, and 1,220 healthy controls. The IL10 genotype was not associated with the incidence of RA, but instead correlated with disease progression, with a significantly higher rate of joint destruction at 2 years observed in patients with a -2849G allele (p less than 0.001). No differences in the invasiveness of fibroblast-like synoviocyte were observed between -2849G and non-G patients, but patients with the G allele, which is associated with high IL10 production, had higher autoantibody titers at baseline. Among 156 RA patients, comprising 68 nonresponders and 88 responders to methotrexate treatment, Rizzo et al. (2006) found a significant association between favorable response and lack of the 14-bp polymorphism in the HLA-G gene (142871). The -14/-14 HLA-G genotype resulted in increased soluble HLA-G and conferred an odds ratio of 2.46 for responsiveness to methotrexate. Rizzo et al. (2006) postulated that the -14/-14 genotype allows the production of adequate levels of the HLA-G antiinflammatory molecule and a consequently positive therapeutic result in RA patients treated with methotrexate. Vyse and Todd (1996) gave a general review of genetic analysis of autoimmune disease, including rheumatoid arthritis. Feldmann et al. (1996) reviewed molecular mechanisms involved in rheumatoid arthritis. - Association with HLA-DRB1 Weyand et al. (1992) found that severity of RA, as reflected in the occurrence of extraarticular manifestations, was associated with homozygosity of a particular HLA-DRB1 allele, namely, 0401 (see 142857). Although genetically homogeneous, the clinical manifestations were heterogeneous; in addition to striking rheumatoid nodules, these included rheumatoid lung disease, rheumatoid vasculitis, Felty syndrome (134750), and rheumatoid vasculitic mononeuritis. HLA-DRB1 alleles encoding the 'shared epitope' are associated with susceptibility to RA (Gregersen et al., 1987). Because peripheral blood T cells have age-inappropriate telomeric erosion in RA, Schonland et al. (2003) examined whether HLA-DRB104 alleles confer risk for T-cell senescence. They found that in healthy individuals, HLA-DRB104 alleles were associated with excessive loss of telomeres in CD4+ T cells and granulocytes, with accelerated telomeric erosion during the first 2 decades of life followed by reduced homeostatic T-cell proliferation during adulthood. Telomeric repair mechanisms were intact in HLA-DRB104+ donors. Schonland et al. (2003) proposed that HLA-DRB104 alleles or genes in linkage disequilibrium regulate stem cell replication and contribute to the accumulation of senescent and autoreactive T cells in RA. Kallberg et al. (2007) investigated gene-gene and gene-environment interactions in rheumatoid arthritis, specifically, the interaction between 2 major genetic risk factors of RA, the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Hill et al. (2003) proposed an etiologic hypothesis that may explain the strong interaction between smoking and HLA-DRB1 SE alleles, that smoking may contribute to citrullination of proteins in the lung and that immune activation against such posttranslationally modified proteins may occur preferentially in individuals carrying HLA-DRB1 SE alleles, since citrullination may specifically increase the affinity between a protein and an SE-containing HLA-DR-beta chain. This hypothesis was made even more attractive by the demonstration by Lundberg et al. (2005) that citrullination of self-antigens may make them more immunogenic and arthritogenic, and that transfer of antibodies to citrullinated fibrinogen (see 134820) enhances the development of antibody-transferred arthritis in mice (Hill et al., 2003). Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB104. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 (600716.0001), and smoking showed the strongest association with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. The Wellcome Trust Case Control Consortium (2010) undertook a large direct genomewide study of association between copy number variants (CNVs) and 8 common human diseases. Using a purpose-designed array, they typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs greater than 500 basepairs. The Wellcome Trust Case Control Consortium (2010) identified several biologic artifacts that led to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed 3 loci where CNVs were associated with disease: HLA for Crohn disease (266600), rheumatoid arthritis, and IDDM (222100); IRGM (608282) for Crohn disease; and TSPAN8 (600769) for type 2 diabetes (125853). In each case the locus had previously been identified in SNP-based studies, reflecting the observation of The Wellcome Trust Case Control Consortium (2010) that most common CNVs that are well-typed on their array are well-tagged by SNPs and so have been indirectly explored through SNP studies. The Wellcome Trust Case Control Consortium (2010) concluded that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. - Association with PTPN22 Begovich et al. (2004) reported the association of RA susceptibility with the minor allele, 1858T, of the R620W SNP in PTPN22. They showed that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with CSK (124095), potentially altering these proteins' normal function as negative regulators of T cell activation. To determine whether other genetic variants in PTPN22 contribute to the development of rheumatoid arthritis, Carlton et al. (2005) sequenced the coding region of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. They then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls, and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls. Analyses of these results predicted 10 common (frequency more than 1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the W620 risk allele (600716.0001) was strongly associated with disease in both the sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, did not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data was stratified by R620W. Additional analyses identified 2 SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least 1 additional variant in the PTPN22 gene region influence RA susceptibility. The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study, using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Their study identified 3 associations for rheumatoid arthritis, including a marker perfectly correlated with the PTPN22 R620W allele. - Association with SLC22A4 Tokuhiro et al. (2003) found that an intronic SNP in the RUNX1 (151385) binding site of SLC22A4 (604190.0001), designated slc2F2, is associated with rheumatoid arthritis. The slc2F2 SNP, found in intron 1, consists of a susceptible T allele and a nonsusceptible C allele. Data suggested that RUNX1 suppresses expression of SLC22A4 and that the susceptible T allele tends to express fewer SLC22A4 transcripts owing to a stronger suppressive effect of RUNX1 on this allele. - Association with PADI4 Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of citrullinating enzymes (peptidylarginine deiminases, encoded by PADI genes) in rheumatoid arthritis. Although no common locus apart from the HLA region was suggested by all linkage studies, some suggested that 1p36 contains a susceptibility locus for rheumatoid arthritis. This region includes 4 peptidylarginine deiminase genes. These genes encode enzymes that are functionally associated with the production of rheumatoid arthritis-specific autoantibodies. The PADIs posttranslationally convert arginine residues to citrulline. Citrullinated epitopes involved in a peptidic link are the most specific targets of rheumatoid arthritis-specific autoantibodies. Citrullination is related to 2 rheumatoid arthritis-specific autoantibody systems: those directed against perinuclear factor/keratin and against Sa. The clinical importance of measuring antibodies to citrullinated peptide and the specificity of autoantibodies suggests a specific role of citrullination and PADIs in the pathophysiology of rheumatoid arthritis. In addition, the appearance of antibodies to citrullinated peptide in sera from affected individuals in the very early phase of disease manifestation implies that citrullination is involved in the triggering phase or the acute phase of the disease. Citrullinated peptides have been identified in rheumatoid arthritis synovial tissue, suggesting the involvement of PADIs in the pathomechanisms of rheumatoid arthritis. Suzuki et al. (2003) used a case-control linkage disequilibrium study to show that of the cluster of PADI genes in the 1p36 region, PADI type 4 (PADI4; 605347) is a susceptibility locus for rheumatoid arthritis. This susceptibility gene could have an important role in the pathogenesis of rheumatoid arthritis by increasing citrullination of proteins in rheumatoid arthritis synovial tissues, leading, in a cytokine-rich milieu, to a break in tolerance to citrullinated peptides processed and presented in the appropriate HLA context. By genomewide association studies in 940 Japanese individuals with rheumatoid arthritis and 940 healthy Japanese controls, Tamiya et al. (2005) confirmed the association between PADI4 and rheumatoid arthritis. - Association with STAT4 In a multistage case-control disease-association analysis of chromosome 2q33 involving a total of 3,149 patients with rheumatoid arthritis and 3,516 controls, Remmers et al. (2007) found that a 4-SNP haplotype (marked by dbSNP rs7574865 and including dbSNP rs11889341, dbSNP rs8179673, and dbSNP rs10181656) in intron 3 of the STAT4 gene was associated with RA. In the North American Rheumatoid Arthritis Consortium (NARAC) series and a replication series, the minor T allele of the most strongly associated SNP (dbSNP rs7574865) was present in 27% of chromosomes of patients with rheumatoid arthritis compared with 22% of those of controls (p = 2.81 x 10(-7)). Metaanalysis including a third patient series yielded a p value of 4.64 x 10(-8). Homozygosity of the risk allele compared to absence of the allele was associated with a 60% increased risk for rheumatoid arthritis, and the risk allele was also associated with systemic lupus erythematosus (SLE; 152700). Martinez et al. (2008) genotyped 575 Spanish patients with RA for dbSNP rs7574865 and confirmed the association with RA (p = 1.2 x 10(-6); odds ratio, 1.59). - Association with Chromosome 6q23 In a genomewide association screen, the Wellcome Trust Case Control Consortium (2007) (WTCCC) identified 9 single SNPs putatively associated with rheumatoid arthritis at a high probability. One SNP, dbSNP rs6920220, was unequivocally replicated in a validation study by Thomson et al. (2007). They demonstrated that this SNP maps to 6q23, between the genes encoding oligodendrocyte lineage transcription factor-3 (OLIG3; 609323) and tumor necrosis factor-alpha-induced protein-3 (TNFAIP3; 191163). Plenge et al. (2007) also identified an SNP at 6q23 (dbSNP rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genomewide association scan and in 5,541 additional case-control samples. Plenge et al. (2007) demonstrated that this SNP is located 3.8 kb from dbSNP rs6920220 identified by Thomson et al. (2007). They showed, furthermore, that these 2 SNP associations are statistically independent, are each reproducible, and defined risk and protective haplotypes for rheumatoid arthritis at 6q23. In U.K. study of 3,962 RA patients and 3,531 healthy controls of Caucasian Northern European descent, Orozco et al. (2009) found 18 SNPs associated with RA in the chromosome 6q23 region. The SNPs showing the strongest association were dbSNP rs6920220 and dbSNP rs13207033, the latter of which was perfectly correlated with dbSNP rs10499194, a SNP previously associated with RA. A number of additional potential RA markers were found, including dbSNP rs5029937, located in intron 2 of the TNFAIP3 gene. Of the 18 associated SNPs, dbSNP rs6920220, dbSNP rs13207033, and dbSNP rs5029937 remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of dbSNP rs6920220 and dbSNP rs5029937 together with the absence of the protective allele of dbSNP rs13207033 was strongly associated with RA (p = 5.2 x 10(-9); OR, 1.86) when compared with carriage of none. - Association with IRF5 Sigurdsson et al. (2007) analyzed 5 SNPs in the IRF5 gene (607218) in Swedish patients with rheumatoid arthritis and found that 4 of the 5 SNPs were associated with RA, including dbSNP rs2004640 (607218.0002). The strongest association was exhibited by dbSNP rs3807306 (p = 0.00063), particularly in a subgroup of anti-CCP-negative RA patients (p = 0.000091), and dbSNP rs3807306 was in linkage disequilibrium (r(2) = 0.67) with dbSNP rs2004640. The association with IRF5 was replicated in a cohort of Dutch RA patients. - Association with CD40 To identify rheumatoid arthritis risk loci in European populations, Raychaudhuri et al. (2008) conducted a metaanalysis of 2 published genomewide association studies totaling 3,393 cases and 12,462 controls. They genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive RA cases and 5,807 matched controls from 8 separate collections. Raychaudhuri et al. (2008) identified a common variant at the CD40 gene locus (dbSNP rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, odds ratio = 0.87). Along with other associations near TRAF1 (601711) and TNFAIP3, Raychaudhuri et al. (2008) concluded that this implied a central role for the CD40 signaling pathway in RA pathogenesis. - Association with CCL21 In a metaanalysis of 2 published genomewide association studies totaling 3,393 cases and 12,462 controls to identify rheumatoid arthritis risk loci in European populations, Raychaudhuri et al. (2008) identified association of the CCL21 gene locus (602737), a gene involved in lymphocyte trafficking, at dbSNP rs2812378 (P = 0.00097 replication, P = 2.8 x 10(-7) overall). They also identified evidence of association at 4 additional gene loci, including MMEL1-TNFRSF14 (dbSNP rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), and KIF5A-PIP4K2C (dbSNP rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall). - Association with CD244 Suzuki et al. (2008) identified a linkage disequilibrium block associated with rheumatoid arthritis in the chromosome 1q region containing multiple SLAM (signaling lymphocyte activation molecule) family genes. In this block, the association peaked at 2 functional SNPs (dbSNP rs3766379 and dbSNP rs6682654) in CD244 (see 605554.0001) in 2 independent RA cohorts from Japan (P = 3.23 x 10(-8) and P = 7.45 x 10(-8)). Suzuki et al. (2008) also identified a Japanese cohort with systemic lupus erythematosus that had a similar genotype distribution as the RA cohorts. - Association with CD2/CD58 To discover new rheumatoid arthritis risk loci, Raychaudhuri et al. (2009) systematically examined 370 SNPs from 179 independent loci with P less than 0.001 in a published metaanalysis of RA genomewide association studies of 3,393 cases and 12,462 controls (Raychaudhuri et al., 2008). The authors used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci. Twenty-two loci with a significant degree of functional connectivity were identified and genotyped in an independent set of 7,957 cases and 11,958 matched controls. Raychaudhuri et al. (2009) validated association at the CD2/CD58 locus (see 153420) (dbSNP rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall). - Association with CD28 Using GRAIL to score candidate susceptibility SNPs identified by Raychaudhuri et al. (2008) for functional relationships to genes in 16 established RA disease loci, followed by genotyping in an independent set of 7,957 cases and 11,958 matched controls, Raychaudhuri et al. (2009) validated association at the CD28 (186760) locus (dbSNP rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall). - Association with PRDM1 Using GRAIL to score candidate susceptibility SNPs identified by Raychaudhuri et al. (2008) for functional relationships to genes in 16 established RA disease loci, followed by genotyping in an independent set of 7,957 cases and 11,958 matched controls, Raychaudhuri et al. (2009) validated association at the PRDM1 (603423) locus (dbSNP rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). - Association with AFF3 Barton et al. (2009) identified an association between SNPs in the AFF3 gene (601464) on chromosome 2q11.2 (dbSNP rs10865035 and dbSNP rs9653422) and susceptibility to rheumatoid arthritis in a combined sample cohort of 6,819 RA cases and 12,650 controls (OR 1.12; p = 2.8 x 10(-7)) from 3 independent U.K. case-control series. - Association with CCR6 Kochi et al. (2010) identified a polymorphism in CCR6 (601835) that was associated with rheumatoid arthritis susceptibility and was validated in 2 independent replication cohorts from Japan (dbSNP rs3093024, a total of 7,069 individuals with rheumatoid arthritis (cases) and 20,727 controls, overall odds ratio = 1.19, p = 7.7 x 10(-19)). Kochi et al. (2010) identified a triallelic dinucleotide polymorphism of CCR6, which they termed CCR6DNP, in strong linkage disequilibrium with dbSNP rs3093024 that showed effects on gene transcription. The CCR6DNP genotype was correlated with expression levels of CCR6 and was associated with the presence of interleukin-17 (IL17; 603149) in the sera of subjects with rheumatoid arthritis. Moreover, CCR6DNP was associated with susceptibility to Graves (275000) and Crohn (see 266600) diseases. Kochi et al. (2010) concluded that CCR6 is critically involved in IL17-driven autoimmunity in human diseases. Stahl et al. (2010) also identified an association at the CCR6 region with rheumatoid arthritis in European populations by performing a metaanalysis of genomewide association studies from a collection of 5,539 autoantibody-positive rheumatoid arthritis cases and 20,169 controls, in which the strongest signal was observed at a SNP in CCR6 (dbSNP rs3093023, p = 3.3 x 10(-7), OR = 1.13). Kochi et al. (2010) noted that the landmark SNP in their Japanese population, dbSNP rs3093024, was in almost absolute linkage disequilibrium with dbSNP rs3093023 in the European population (r(2) greater than 0.99). ANIMAL MODEL Studies supporting a role for HLA-DQ polymorphism in human rheumatoid arthritis were supported by Nabozny et al. (1996) and Bradley et al. (1997). Nabozny et al. (1996) demonstrated that mice transgenic for HLA-DQ8, a DQ allele associated with susceptibility to RA, developed severe arthritis after type II collagen immunization. Bradley et al. (1997) generated mice transgenic for HLA-DQ6, an allele associated with a nonsusceptible haplotype, and found that the DQ6 mice were resistant to collagen-induced arthritis. They also generated double-transgenic mice expressing both DQ6 and DQ8 molecules (representing the more prevalent condition found in humans, where heterozygosity at the DQ allele is common). See HLA-DQA1 (146880). Pristane is a nonimmunogenic synthetic oil that, after a single subcutaneous injection into rats of the DA strain, induces arthritis restricted to peripheral joints with a chronic relapsing disease course (Vingsbo et al., 1996). To identify genes involved in the control of chronic arthritis, Vingsbo-Lundberg et al. (1998) made crosses between susceptible DA rats and resistant E3 rats and analyzed the progeny with microsatellite markers covering the entire rat genome. The results showed that different arthritis phenotypes are associated with different chromosomal loci. Loci on chromosomes 4 and 6 (Pia2 and Pia3) influenced arthritis onset, whereas a locus on chromosome 12 (Pia4) was associated with severity and joint erosion. Vingsbo-Lundberg et al. (1998) found that chronicity was associated with a different set of loci, one on chromosome 4 and the other on chromosome 14 (Pia5, Pia6). These findings in pristane-induced arthritis (PIA) in rats demonstrate that different phases of a chronic self-perpetuating disease that mimics RA are associated with distinct sets of genes. Holm et al. (2001) produced a congenic strain for Oia3, a genetic factor originally identified as an oil-induced arthritis (OIA) quantitative trait locus (QTL) in arthritis-prone DA rats. A 46-cM telomeric region of chromosome 10 encompassing Oia3 was transferred from DA rats to MHC-identical but minutely arthritis-susceptible LEW.1AV1 rats by selective breeding. Two weeks after intradermal injection, the endogenous cholesterol precursor squalene induced T cell infiltration into joints and macroscopic arthritis in Oia3-congenic rats and DA rats, whereas LEW.1AV1 rats were almost resistant. Arthritis onset coincided with arrested body weight gain and increased plasma levels of the inflammation markers fibrinogen and alpha-1-acid glycoprotein. Congenic rats displayed intermediate phenotypes compared with the 2 parental strains, and similar to rheumatoid arthritis in humans, female preponderance was observed in Oia3-congenic rats. Finally, recombinant rat strains were constructed and were used to map a susceptibility gene(s) in females to a telomeric 4- to 19-cM Oia3 subregion. Barton et al. (2001) investigated linkage to 5 regions homologous to those identified in animal models of inflammatory arthritis in RA-affected sib-pair families. Linkage to 17q22 syntenic to a susceptibility locus common to 2 experimental rat models (oil-induced and collagen-induced arthritis) was detected in 200 RA-affected sib-pair families and replicated in a further 100 RA-affected sib-pair families. Linkage to additional markers mapping to the area refined the extent of linkage to a 4-cM region. Association to one of the markers (D17S807) was demonstrated in this cohort using extensions of the transmission disequilibrium test. Association to two 2-marker haplotypes, including this marker, was detected in an independent cohort of single-case RA families, further refining the region to 1 cM. Sakaguchi et al. (2003) reported that the SKG strain, which is derived from a closed breeding colony of BALB/c mice, spontaneously develops chronic arthritis. Joint swelling with hyperemia became macroscopically evident in SKG mice at about 2 months of age, initially at a few interphalangeal joints of the forepaws, then progressing in a symmetrical fashion to swelling of the other finger joints of the forepaws and hindpaws and larger joints (wrists and ankles). Knee, elbow, shoulder, or vertebral joints were rarely affected except for the joint at the base of the tail in aged SKG mice. Radiographic examination revealed destruction and fusion of the subchondral bones, joint dislocation, and osteoporosis by 8 to 12 months of age. Despite suffering from such severe chronic arthritis, most SKG mice survived well to 1 year of age, generally with more severe arthritides in females. Sakaguchi et al. (2003) found that this arthritis is an autosomal recessive trait. They found a tryptophan-to-cysteine substitution at residue 163 (W163C) at the start of the second SH2 domain of ZAP70 (176947). Altered signal transduction from T-cell antigen receptor (see 186740) through the aberrant ZAP70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Sakaguchi et al. (2003) speculated that thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might be crucial to the development of disease in a subset of patients with rheumatoid arthritis. Nurieva et al. (2003) found that mice deficient in inducible costimulator (ICOS; 604558) were completely resistant to collagen-induced arthritis, developing no joint tissue inflammation and exhibiting reduced anticollagen IgM and IgG2a antibodies. Spleen cells from Icos-null mice produced markedly reduced levels of interleukin-17 (IL17; 603149) in response to collagen, and Icos was shown to significantly increase Il17 production by activated T cells. Nurieva et al. (2003) concluded that ICOS regulates expression of IL17 and is essential for collagen-induced arthritis. Collagen type II (120140)-induced arthritis is a Cd4-positive T cell-dependent chronic inflammation in susceptible DBA/1 mice and represents a model for human rheumatoid arthritis. Seo et al. (2004) found that an agonistic anti-4-1BB (TNFRSF9; 602250) monoclonal antibody (Mab) inhibited development of collagen type II-induced arthritis, as well as established disease, in DBA/1 mice. The Mab suppressed both serum antibody to collagen type II and Cd4-positive T-cell recall responses to the antigen. Mab treatment induced massive, antigen-dependent clonal expansion of Ifng-producing Cd11c (ITGAX; 151510)-positive/Cd8-positive T cells and the accumulation of indoleamine 2,3-dioxygenase (INDO; 147435) in Cd11b (ITGM; 120980)-positive monocytes and Cd11c-positive dendritic cells. Treatment with anti-Ifng or an inhibitor of Indo reversed the beneficial effects. Seo et al. (2004) concluded that expansion of a new population of Cd11c-positive/Cd8-positive T cells producing large amounts of Ifng mediated the suppression of collagen-induced arthritis through an Indo-dependent mechanism. Camps et al. (2005) used structure-based drug design to develop a potent small molecule inhibitor of PIK3CG (601232), a phosphoinositide-3-kinase that regulates inflammation. The inhibitor was referred to as AS-605240. Oral administration of AS-605420 to mice resulted in reduced clinical and histologic signs of collagen II-antibody-induced arthritis, a lymphocyte-independent mouse model of rheumatoid arthritis associated with neutrophil activation. Oral AS-605240 also resulted in reduced joint inflammation and damage in a second distinct murine model of lymphocyte-dependent rheumatoid arthritis induced by direct collagen II injection. Camps et al. (2005) concluded that PIK3CG inhibition operated on both the neutrophil and lymphocyte arms of chemokine signaling pathways, and thus may be of therapeutic value in various chronic inflammatory diseases. Kawane et al. (2006) showed that DNase II (see 126350)-null/interferon type I receptor (IFNIR)-null mice and mice with an induced deletion of the DNase II gene developed a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anticyclic citrullinated peptide antibody, rheumatoid factor, and matrix metalloproteinase-3 (see 185250). Early in the pathogenesis, expression of the gene encoding tumor necrosis factor (TNF)-alpha (191160) was upregulated in the bone marrow, and administration of anti-TNFA antibody prevented the development of arthritis. Kawane et al. (2006) concluded that their results indicated that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNFA, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis. ► ▼ PROSTATE CANCER, HEREDITARY, 7; HPC7* 610321 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. MAPPING Lange et al. (2006) performed a genomewide linkage scan on 71 informative families with 2 or more men with aggressive prostate cancer. When only men with aggressive prostate cancer were coded as affected, statistically significant evidence for linkage at chromosome 15q12 was detected, with a lod score of 3.49 (genomewide p = 0.005). The evidence for linkage increased when analyses were restricted to 65 Caucasian American pedigrees (lod score, 4.05) or to 42 pedigrees with 2 confirmed aggressive cases (lod score, 4.76). No significant linkage was found to either 7q32 or 19q12, two quantitative trait loci that have been associated with prostate cancer aggressiveness (see 607592). FitzGerald et al. (2010) performed genomewide SNP linkage analysis of 96 families with hereditary prostate cancer, each of which had 1 or more first-degree relatives with colon cancer. The strongest linkage signal was identified at chromosome 15q14 for a 31.04-cM interval spanning dbSNP rs732165 and dbSNP rs1989223, when both prostate and colon cancer phenotypes were considered to be affected in families with 2 or more colon cancer cases (recessive HLOD = 3.88). ► ▼ PROSTATE CANCER, HEREDITARY, X-LINKED 1; HPCX1 300147 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Xu et al. (1998) presented evidence for the location of a prostate cancer susceptibility gene, which they symbolized HPCX, on Xq27-q28. Heterogeneity estimates suggested that the gene accounts for approximately 16% of hereditary prostate cancer cases. The finding was consistent with the results of a previous population-based study suggesting an X-linked mode of inheritance of prostate cancer. Linkage to Xq27-q28 was observed in a combined study population of 360 prostate cancer families collected at 4 independent sites in North America, Finland, and Sweden. A maximum 2-point lod score of 4.60 was observed with DXS1113 at theta = 0.26 in the combined data set. Parametric multipoint and nonparametric analyses provided results consistent with the 2-point analysis. The estimation of the proportion of X-linked families appeared to be the same in each family collection. A candidate prostate cancer susceptibility gene on the X chromosome is the androgen receptor gene (AR; 313700). AR, however, is located at Xq12, over 50 cM from the region implicated in the study of Xu et al. (1998). Peters et al. (2001) reported on linkage analysis at the putative HPCX locus in an independent set of 186 prostate cancer families. In 81 families with no evidence of male-to-male transmission, they found a lod score of 1.062 at theta = 0.28 with DXS984. Although this analysis did not show statistically significant evidence for the linkage of prostate cancer susceptibility to Xq27-q28, the results were considered consistent with a small percentage of families being linked to this region. Cancel-Tassin et al. (2001) examined evidence for linkage to the HPCX locus in 64 (37 previously reported and 27 newly identified) families from southern and western Europe with at least 3 affected individuals with prostate cancer and an average age at diagnosis of 66.4 years. Using both parametric and nonparametric linkage methods, no significant evidence of linkage was observed. A subset of 18 pedigrees without male-to-male transmission showed negative or low positive 2-point lod scores and negative multipoint lod scores across the entire region. Farnham et al. (2005) performed linkage analysis on 143 Utah pedigrees for the HPCX prostate cancer susceptibility locus. In a dataset containing pedigrees having no more than 5 generations, a multipoint theta lod score of 2.74 (p = 0.0002) was observed, which was considered statistically significant after correction for multiple testing. Theta lod is a linkage statistic that is analogous to a 2-point lod score but utilizes full multipoint haplotype information. For both the full-structure pedigrees (up to 7 generations) and the smaller subpedigrees, the linkage evidence was much reduced. By linkage disequilibrium and haplotype analysis of Finnish families with X-linked prostate cancer with no male-to-male transmission, Baffoe-Bonnie et al. (2005) refined the HPCX locus to a 150-kb region on Xq27-q28 between markers D3S2390 and bG82i1.0. ► ▼ PROSTATE CANCER, HEREDITARY, 10; HPC10 611100 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. MAPPING Amundadottir et al. (2006) reported a common variant on 8q24 associated with prostate cancer, discovered in a genomewide linkage scan in 871 Icelandic men with prostate cancer that grouped into 323 extended families. The linkage signal had a maximum lod score of 2.11 (D8S529 at 148.25 cM). To refine the location of the linkage signal, they performed an association study and found the strongest association to prostate cancer for allele -8 of the microsatellite DG8S737, with an odds ratio (OR) of 1.79. Of SNPs identified within the linkage disequilibrium block that contains DG8S737, allele A of dbSNP rs1447295 showed the strongest association with prostate cancer (OR = 1.72, P = 1.7 x 10(-9)). The result was replicated in 3 case-control series of European ancestry in Sweden and the United States. Combining results from the 3 case-control groups of European ancestry gave an estimated OR of 1.62 (P = 2.7 x 10(-11)) for DG8S737 -8 and an OR of 1.51 (P = 1.0 x 10(-11)) for dbSNP rs1447295. Amundadottir et al. (2006) found that about 19% of affected men and 13% of the general population carried at least 1 copy of allele -8, yielding a population attributable risk (PAR) of about 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population were found to be carriers. This led to a greater estimated PAR (16%) for the African American group, which may contribute to the higher incidence of prostate cancer in African American men than in men of European ancestry. Freedman et al. (2006) performed a whole-genome admixture scan in 1,597 African Americans and identified a 3.8-Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer (lod = 7.1). The increased risk associated with African ancestry at 8q24 was greater in men diagnosed before 72 years of age (P less than 0.00032), and Freedman et al. (2006) suggested that this finding supports the epidemiologic observation that the higher risk for prostate cancer in African Americans is greater in younger men and attenuates with older age. The authors noted that the same region had been identified by Amundadottir et al. (2006) through linkage analysis of prostate cancer, followed by fine mapping. Freedman et al. (2006) strongly replicated this association (P less than 4.2 x 10(-9)) but found that the previously described alleles (DG8S737, dbSNP rs1447295) did not explain more than a fraction of the admixture signal. Following up on the study of Amundadottir et al. (2006), which identified the correlated variants allele A dbSNP rs1447295 and allele -8 of microsatellite marker DG8S737 associated with prostate cancer, Gudmundsson et al. (2007) performed a genomewide association scan of 1,453 affected Icelandic individuals and 3,064 controls using microarray analysis followed by 4 replication studies. The dbSNP rs1447295 gave the most significant results for association (OR = 1.71, P = 1.6 x 10(-14)). They constructed a 14-SNP haplotype that efficiently tagged a susceptibility variant, dbSNP rs16901979, relatively uncommon (2 to 4%) in individuals of European descent but very common (approximately 42%) in African Americans. The dbSNP rs16901979 variant showed a stronger association with affected individuals who had an earlier age at diagnosis. Gudmundsson et al. (2007) estimated the PAR of the dbSNP rs16901979 A allele alone to be 24% in African Americans and approximately 13% in populations of European ancestry; with updated estimates for the effect of DG8S737 -8 in African Americans, the 2 variants had a combined estimated PAR of 31% in that population. The authors suggested that these 2 variants could account for a large fraction of the excess of prostate cancer rates in African Americans relative to European Americans. The genomic region containing dbSNP rs16901979 did not contain any known genes or microRNAs. Following up on the admixture scan of Freedman et al. (2006) in African Americans with prostate cancer, Haiman et al. (2007) genotyped 2,973 SNPs in up to 7,518 men with or without prostate cancer from African American, Japanese American, Native Hawaiian, Latino, and European American populations. They identified 7 risk variants, 5 theretofore undescribed, spanning 430 kb and each independently predicting risk for prostate cancer. The strongest association was for dbSNP rs6983561 (P = 7.9 x 10(-19)). The variants defined common genotypes that span more than a 5-fold range of susceptibility to prostate cancer in some populations. None of the variants aligned to a known gene or altered the protein sequence of an encoded protein. In a genomewide association analysis using 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), Yeager et al. (2007) identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal, dbSNP rs6983267, was 70 kb centromeric to the previously reported dbSNP rs1447295, but showed little evidence of linkage disequilibrium with it. A combined analysis with 4 additional studies (total: 4,296 cases and 4,299 controls) confirmed association with prostate cancer for dbSNP rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote OR: 1.26, 95% confidence interval: 1.13-1.41; homozygote OR: 1.58, 95% confidence interval: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (dbSNP rs1447295, P = 1.41 x 10(-11); dbSNP rs6983267, P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the 2 markers, indicated the presence of at least 2 independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. Yeager et al. (2007) estimated that the PAR of the new locus, marked by dbSNP rs6983267, is higher than the locus marked by dbSNP rs1447295 (21% versus 9%). They noted that dbSNP rs6983267 has an overall population frequency in northern Europeans of 50% for the at-risk G allele. Witte (2007) reviewed the studies of Amundadottir et al. (2006), Freedman et al. (2006), Gudmundsson et al. (2007), Haiman et al. (2007), and Yeager et al. (2007). Combining results for dbSNP rs1447295, which resides in a region designated 'region 1,' across the studies of Gudmundsson et al. (2007), Haiman et al. (2007), and Yeager et al. (2007) indicated an extraordinarily strong association, with an adjusted P value of 4 x 10(-29). However, Witte (2007) noted that, as in the studies of Amundadottir et al. (2006) and Freedman et al. (2006), relatively weak associations were observed in this region among African Americans. Merging the findings for dbSNP rs16901979, within region 2 located approximately 350 kb upstream of region 1, gave an adjusted P value of 1 x 10(-19). Combining results for dbSNP rs6983267, within region 3 between regions 1 and 2, from the 3 later studies gave an adjusted P value of 1 x 10(-11). Witte (2007) concluded that SNPs across all 3 neighboring regions seem to contribute independently to the 8q24 signal, and the combined effects of SNPs across regions closely follow a multiplicative model. In a large genomewide association study to search for common variants with moderate risk, Thomas et al. (2008) confirmed the association of 2 independent SNPs at 8q24 with prostate cancer, dbSNP 4242382 (P = 1.12 x 10(-4)) and dbSNP rs6983267 (P = 3.92 x 10(-4)). Eeles et al. (2008) likewise confirmed the association, identifying 20 SNPs on 8q24 with P less than 10(-6). Yeager et al. (2008) used next-generation sequencing technology to conduct a resequence analysis of a 136-kb region on chromosome 8q24 in 39 cases of advanced prostate cancer and 40 controls of European origin. The study yielded a comprehensive catalog of common SNPs within this region, including 442 novel SNPs, as well as the pattern of linkage disequilibrium across the region. Yeager et al. (2008) suggested that their results would be useful in choosing SNPs for fine mapping of association signals in 8q24 in prostate and colorectal cancer and for investigations of the functional consequences of select common variants. Several groups found association of the prostate cancer risk-associated SNP dbSNP rs6983267 with susceptibility to colorectal cancer; see CRCS2, 611469. Yeager et al. (2009) reported a genomewide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. They identified a new association with prostate cancer risk on chromosome 8q24 (dbSNP rs620861, P = 1.3 x 10(-10), heterozygote OR, 1.17, 95% CI 1.10-1.24; homozygote OR, 1.33, 95% CI 1.21-1.45). The risk is associated with the C allele of this SNP. Because previous studies had identified multiple loci on 8q24 associated with prostate cancer risk, Olama et al. (2009) performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. They confirmed associations at 3 previously reported loci and identified additional loci in 2 other linkage disequilibrium blocks (dbSNP rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); dbSNP rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in 5 linkage disequilibrium blocks were independently associated with prostate cancer susceptibility. The 2 highest were dbSNP rs6983267 with a per allele OR of 1.26, 95% CI of 1.18-1.35, and P value of 6.2 x 10(-23); and dbSNP rs10090154, with a per-allele OR of 1.47 and P value of 6.8 x 10(-24). Gudmundsson et al. (2009) reported a prostate cancer genomewide association follow-up study. They identified association with 2 SNPs on chromosome 8q24.21, dbSNP 16902094G (OR 1.21, P = 6.2 x 10(-15)) and dbSNP rs445114T (OR = 1.14, P = 4.7 x 10(-10)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, Gudmundsson et al. (2009) estimated that carriers in the top 1.3% of the risk distribution are at 2.5 times greater risk of developing the disease than members of the general population. ► ▼ PROSTATE CANCER, HEREDITARY, 15; HPC15 611959 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Eeles et al. (2008) conducted a genomewide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (less than 0.5 ng/ml). They analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. They identified 3 single-nucleotide polymorphisms (SNPs) on chromosome 19 that were significantly associated with prostate cancer. Of these, the most significantly associated (P = 1.5 x 10(-18)) was dbSNP rs2735839. This SNP is located between KLK2 (147960), encoding prostatic kallikrein, and KLK3 (176820), encoding prostate-specific antigen (PSA), a serine protease that liquifies semen and is used as a serum marker in screening and disease progression. Following up on the paper by Eeles et al. (2008), Ahn et al. (2008) evaluated the association of 24 tag SNPs in the KLK region, including SNPs in KLK3 and nearby genes KLK1 (147910), KLK2, and KLK15 (610601), with prostate cancer risk in 1,172 prostate cancer cases and 1,157 controls in men of European ancestry from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, in which serum PSA was used in screening for this disease. Ahn et al. (2008) also examined the prostate cancer risk relationship for 12 of these tag SNPs in the KLK3 region in 4 independent studies from diverse populations including 4,020 prostate cancer cases and 4,028 controls, as a component of Cancer Genetic Markers of Susceptibility (CGEMS) GWAS. Ahn et al. (2008) found that none of the 24 tag SNPs in the KLK region showed strong evidence for association with prostate cancer in the PLCO study, and none of the SNPs in the KLK3 region were significant in the CGEMS combined analyses. However, 2 of the tag SNPs (dbSNP rs1058205 and dbSNP rs2735839), located in the 3-prime untranslated region of KLK3 and in high linkage disequilibrium (LD), along with 4 other variants upstream of the gene and several downstream in high LD, were strongly associated with serum PSA concentrations. Only dbSNP rs2735839 remained significantly associated with PSA concentration when all these SNPs were simultaneously included in the multivariate model. When Ahn et al. (2008) preferentially limited the men in the control group in the PLCO Trial GWAS to those with PSA less than 0.5 ng/ml, prostate cancer risk associations were greater by more than 5-fold for some genotypes, even though the same SNPs showed no clear association when the full control group was used. KLK SNPs were not associated with prostate cancer risk in PLCO when only cases and controls with high PSA levels or only cases and controls with low PSA levels were compared. Ahn et al. (2008) concluded that SNPs in the KLK3 region were not associated with prostate cancer risk in their series of 5 case-control studies. Furthermore, with widespread use of PSA in clinical practice, even modest associations observed between KLK3 SNPs and prostate cancer risk in some epidemiologic studies may be due to PSA-directed differential identification of prostate cancer cases with particular KLK3-PSA profiles. Eeles et al. (2008) replied to the comments by Ahn et al. (2008) with a report of an analysis of dbSNP rs2735839 in 13 further case-control studies as part of the PRACTICAL Consortium. The estimated per allele OR for prostate cancer associated with dbSNP rs2735839 was 0.89 (95% CI = 0.83-0.95; P = 0.0007), very close to their original estimate. Eeles et al. (2008) also noted that when data from the 5 CGEMS studies were combined, the per allele OR was also remarkably similar (per allele OR = 0.90, 95% CI = 0.83-0.90, P = 0.01), although this was not formally significant using the 4-degree-of-freedom test given by Ahn et al. (2008). If the combined results from stage 2 of their initial study (Eeles et al., 2008), PRACTICAL, and CGEMS are combined, the overall evidence of association reached genomewide levels of significance (P less than 10(-8)). ► ▼ TYPE 2 DIABETES MELLITUS 2; T2D2 601407 only shown in mice By screening over 4,000 individuals from a Swedish-speaking population isolate in the Botnia region of western Finland, Mahtani et al. (1996) identified 26 families (comprising 217 individuals) enriched for NIDDM (125853) and performed a genomewide scan using nonparametric linkage analysis. They found no significant evidence for linkage when the families were analyzed together, but strong evidence for linkage when families were classified according to mean insulin levels in affected individuals in oral glucose tolerance tests. Specifically, families with the lowest insulin levels showed significant linkage to chromosome 12 near D12S1349. This region contains the gene causing the rare, dominant, early-onset form of diabetes, designated MODY3 (600496). Unlike MODY3 families, the Finnish families with low insulin had an age of onset typical for NIDDM (mean = 58 years). Mahtani et al. (1996) inferred the existence of a gene NIDDM2 causing noninsulin-dependent diabetes mellitus associated with low insulin secretion and suggested that NIDDM2 and MODY3 may represent different alleles of the same gene. Lehto et al. (1997) found that NIDDM2, like MODY3, is characterized by a reduced insulin secretory response that subsequently progresses to diabetes. This, together with the common site of the gene on 12q, suggested to them that NIDDM2 with its late age of onset was due to an allelic mutation in the HNF1A gene (142410), which has been found to be mutant in MODY3. Shaw et al. (1998) reported significant linkage with the NIDDM2 region on 12q24.2 in a single pedigree in Australia in which type II diabetes segregated in an autosomal dominant pattern of inheritance. The family was negative for mutations in the HNF1A gene. To assess whether the NIDDM2 locus can be detected in the U.S. population, Bektas et al. (1999) scanned 12q for linkage to diabetes in 26 Caucasian and 6 non-Caucasian multigenerational families with early-onset autosomal dominant type II diabetes. These pedigrees were negative for mutations in the HNF1A gene, thereby excluding MODY3. The mean age at diagnosis of diabetes for affected members was 37 +/- 18 years. While no evidence for linkage was detected at the NIDDM2 locus, a linkage peak was observed 50 cM centromeric to NIDDM2 between markers D12S375 and D12S1052. In a nonparametric analysis, the combined lod score was 2.9 at D12S375, and increased to 3.8 (P = 0.007) among Caucasian families. A further increase in significance was observed in pedigrees with poor insulin response. Suggestive evidence of linkage was also detected by a parametric analysis. Bektas et al. (1999) interpreted their data as indicating that the NIDDM2 locus does not play a major role in early-onset autosomal dominant type II diabetes. They suggested that a previously undetected type II diabetes locus exists 50 cM centromeric to NIDDM2 on 12q. Lindgren et al. (2002) extended the genomewide scan of Mahtani et al. (1996) to include 32 additional families, updating the affectation status and fine-mapping regions of interest. In the analysis of all 58 families, they identified suggestive linkage to 1 region, 9p13-q21 (nonparametric linkage score, 3.9; P less than 0.0002). When chromosome 12q24 was analyzed in only the 32 additional families, a nominal P value of less than 0.04 was observed. Together with data from other published genomewide scans, these findings lent support to the hypothesis that regions on 9p13-q21 and 12q24 may harbor susceptibility genes for type II diabetes. Kato et al. (2006) performed a region-wide association analysis on 12q15-q22 using more than 500 SNPs in 1,492 unrelated Japanese individuals and identified an association between type II diabetes and a 13.6-kb haplotype block that includes the entire SOCS2 gene (605117). Five SNPs in the 5-prime region of the SOCS2 gene were significantly associated with type II diabetes. Kato et al. (2006) concluded that SOCS2 may play a role in susceptibility to type II diabetes in the Japanese. ► ▼ TYPE 2 DIABETES MELLITUS 4; T2D4 608036 only shown in mice For a phenotypic description and a discussion of genetic heterogeneity of noninsulin-dependent diabetes mellitus (NIDDM), see 125853. Reynisdottir et al. (2003) performed a genomewide linkage study of type II diabetes in the Icelandic population. A list of type II diabetics was cross-matched with a computerized genealogic database clustering 763 type II diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to chromosome 5q34-q35.2 (lod of 2.90) in all diabetics. Reynisdottir et al. (2003) stratified the group as obese or nonobese. A nonparametric multipoint linkage analysis yielded linkage to the same region with lod of 3.64 in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a lod of score of 3.48 in the same region, whereas conditioning on paternal transmission led to a substantial drop in the lod score. Reynisdottir et al. (2003) also observed potential interactions between the 5q locus and type II diabetes susceptibility loci on chromosomes 10 (Duggirala et al., 1999) and 12 (NIDDM2; 601407). ► ▼ PROSTATE CANCER, HEREDITARY, 14; HPC14 611958 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. In a large genomewide association study (GWAS) of prostate cancer, Thomas et al. (2008) detected a single-nucleotide polymorphism (SNP) on chromosome 11q13, dbSNP rs10896449, the G allele of which was significantly associated with prostate cancer risk (P = 1.76 x 10(-9)). The dbSNP rs10896449 SNP is located 67 kb upstream of a gene overexpressed in myeloma, MYEOV (605625). Eeles et al. (2008) conducted a genomewide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (less than 0.5 ng/ml). They analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. Eeles et al. (2008) identified a SNP on chromosome 11, dbSNP rs7931342, that was significantly associated with prostate cancer risk (P = 1.7 x 10(-12)). They described the region on chromosome 11 in which the SNP dbSNP rs7931342 is located as 'a gene desert.' In a prostate cancer genomewide association follow-up study, Gudmundsson et al. (2009) refined a previous association signal on 11q13 with dbSNP rs11228565A (odds ratio = 1.23, P = 6.7 x 10(-12)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, Gudmundsson et al. (2009) estimated that carriers in the top 1.3% of the risk distribution are at 2.5 times greater risk of developing the disease than members of the general population. ► ▼ PROSTATE CANCER, HEREDITARY, X-LINKED 2; HPCX2 300704 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Gudmundsson et al. (2008) conducted a genomewide single-nucleotide polymorphism (SNP) association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: dbSNP rs5945572 on Xp11.22, and dbSNP rs721048 on 2p15 (HPC12; 611868). The A allele of dbSNP rs5945572 showed the strongest association of markers on the X chromosome in analysis of the Icelandic samples (allele-specific OR = 1.21, P = 3.36 x 10(-4)). Combining results from the Icelandic group with those from 7 other prostate cancer study groups of European descent resulted in achievement of genomewide significance for dbSNP rs5945572: OR = 1.23, P = 3.95 x 10(-13). The dbSNP rs5945572 SNP is located on Xp11.22, with the closest genes being NUDT10 (300527) and NUDT11 (300528) on Xp11.23. The A allele correlated with a population-attributable risk (PAR) of approximately 7% in individuals of European descent. Eeles et al. (2008) conducted a genomewide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (less than 0.5 ng/ml). Eeles et al. (2008) analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. Eeles et al. (2008) identified association of a SNP on chromosome Xp, dbSNP rs5945619 (P = 1.5 x 10(-9)), between NUDT10 and NUDT11 (about 2 kb upstream of the latter). ► ▼ PROSTATE CANCER, HEREDITARY, 9; HPC9 610997 only shown in mice For a general discussion of hereditary prostate cancer, see 176807. Lange et al. (2003) performed linkage analysis on 175 pedigrees with prostate cancer, most of whom contained 3 or more affected individuals. A candidate locus was identified on chromosome 17q (nonparametric lod score of 2.36), with strongest evidence coming from a subset of pedigrees with 4 or more affected individuals (nonparametric lod score of 3.27). By linkage analysis of 453 pedigrees with prostate cancer, including the 175 pedigrees analyzed by Lange et al. (2003), Lange et al. (2007) found linkage to 17q21-q22 (maximum lod score of 2.99 near marker D17S1820). A subset of 147 families with 4 or more cases of prostate cancer and an average age at diagnosis of less than or equal to 65 years resulted in a maximum lod score of 5.49 near the same marker. ► ▼ OVARIAN CANCER 167000 only shown in mice Oncology: Ovarian cancer; Dysgerminoma; Ovarian papillary adenocarcinoma; Serous ovarian cystadenocarcinoma; Breast cancer Lab: Frequent loss of heterozygosity at 6q24-q27 Inheritance: Autosomal dominant A number sign (#) is used with this entry because ovarian cancer has been associated with somatic changes in several genes, including OPCML (600632), PIK3CA (171834), AKT1 (164730), CTNNB1 (116806), RRAS2 (600098), CDH1 (192090), ERBB2 (164870), and PARK2 (602544). See also 607893 for an ovarian cancer susceptibility locus (OVCAS1) that has been mapped to chromosome 3p25-p22. Familial ovarian cancer may be part of other cancer syndromes. See susceptibility to familial breast-ovarian cancer 1 and 2 (604370 and 612555), due to mutations in the BRCA1 (113705) and BRCA2 (600185) genes, respectively; and Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1; 120435), due to mutations in DNA mismatch repair genes such as MSH2 (609309), MSH3 (600887), MSH6 (600678), and MLH1 (120436). DESCRIPTION Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to the biology of the disease, which is a principal determinant of outcome (Auersperg et al., 2001). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008). INHERITANCE There are several early reports of familial ovarian cancer showing autosomal dominant inheritance. Some of these families may have had the breast-ovarian cancer syndrome or Lynch syndrome. Liber (1950) described a family with histologically proven papillary adenocarcinoma of the ovary in 5 sisters and their mother. Jackson (1967) reported a Jamaican family in which grandmother, mother, and daughter developed ovarian tumors; 2 tumors were known to have been dysgerminomas (see 603737). Lewis and Davison (1969) described a family in which 5 of 6 sisters and their mother had ovarian cancer. One of the 5 had a malignant ovarian cyst but subsequently died of colon cancer. Prophylactic oophorectomy was performed in the sixth sister and in 5 females of the following generation. Li et al. (1970) reported a family in which 7 women, including 4 sisters, had ovarian carcinoma. Ovarian cancer was suspected in 3 other women of the family. Philip (1979) described a family with multiple cases of poorly differentiated cystadenocarcinoma of the ovary. The 4 relatives with ovarian carcinoma were the proband's mother, maternal aunt, that woman's daughter, and the daughter of another maternal aunt. CYTOGENETICS Whang-Peng et al. (1984) performed cytogenetic studies on ovarian tumor tissue from 44 patients with various forms of epithelial ovarian cancer. All 44 samples had numerical abnormalities, and 39 had structural abnormalities involving multiple chromosomes. Clone formation and the number of chromosomes involved in structural abnormalities increased with duration of disease and were more extensive in patients treated with chemotherapy compared to patients treated with surgery alone. Aneuploidy was observed in all patients and there was considerable variation in the chromosome numbers, often ranging from diploidy to triploidy to tetraploidy. MAPPING - Chromosome 2q22.1 Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, Song et al. (2009) evaluated 11 of the most significant loci from a previously reported breast cancer genomewide association study for association with invasive ovarian cancer (Easton et al., 2007). The 11 SNPs were initially genotyped in 2,927 invasive ovarian cancer cases and 4,143 controls from 6 ovarian cancer case-control studies. Only dbSNP rs4954956 located less than 7.0 kb upstream of the NXPH2 gene (604635) was significantly associated with ovarian cancer risk both in the replication study and in combined analysis of 5,353 patients and 8,453 controls. This association was stronger for the serous histologic subtype (p = 0.0004; OR, 1.14) than for all types of ovarian cancer (p = 0.05; OR, 1.07). - Chromosome 6q25 Saito et al. (1992) examined loss of heterozygosity (LOH) in 70 ovarian tumors using 9 RFLP markers located at chromosome 6q24-q27. Among 33 informative serous cancers, 17 (52%) showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors showed LOH. A detailed deletion map delineated a 1.9-cM region, within which the authors postulated the existence of a tumor suppressor gene involved in ovarian carcinoma. In 54 fresh and paraffin-embedded invasive ovarian epithelial tumor tissues, Colitti et al. (1998) used tandem repeat markers on chromosome 6q25 to delineate a 4-cM minimal region of LOH of 6q25.1-q25.2 between markers D6S473 and D6S448. Loss of heterozygosity was observed more frequently at the loci defined by marker D6S473 (14 of 32 informative cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). LOH at D6S473 correlated significantly both with serous compared to non-serous ovarian tumors (p = 0.040), and with high-grade compared to low-grade specimens (p = 0.023). - Chromosome 11q25 Loss of heterozygosity studies indicated that a tumor suppressor gene associated with sporadic ovarian cancer may reside at chromosome 11q25 (Gabra et al., 1996; Launonen et al., 1998). In tumor tissue from 118 individuals with epithelial ovarian cancer, Sellar et al. (2003) observed a peak LOH rate of 49% (36 of 74 informative cases) across 11q25 at D11S4085. Conversely, LOH analysis of 39 pairs of DNA from individuals with colorectal cancer (see 114500) and normal DNA showed an LOH rate at D11S4085 of only 23% (6 of 26 informative cases), with no evidence of complete LOH. - Chromosome 17p Eccles et al. (1990) found LOH of chromosome 17p in 69% of 16 epithelial ovarian cancer tumors. Schultz et al. (1996) identified 2 genes, OVCA1 (DPH1; 603527) and OVCA2 (607896), within a minimum region of allelic loss on chromosome 17p13.3 in a cohort of ovarian tumors. Expression of OVCA1 and OVCA2 was reduced or undetectable in ovarian tumor tissue and cell lines compared with normal ovarian epithelial cells. The findings provided evidence for 1 or more possible tumor suppressor genes on chromosome 17p distinct from the TP53 gene (191170). Phillips et al. (1996) also identified the DPH1 (OVCA1) gene within the region on chromosome 17p13.3 that is deleted in 80% of all ovarian epithelial malignancies. They suggested that it may act as a tumor suppressor gene. - Chromosome 17q Chromosome 17q contains several genes implicated in ovarian cancer: the BRCA1 gene (113605) on 17q21, the ERBB2 gene (164870) on 17q21.1, and the SEPT9 gene (604061) on 17q25. Eccles et al. (1990) found LOH of 17q in 77% of 16 epithelial ovarian cancer tumors. Godwin et al. (1994) examined normal and tumor DNA samples from 32 patients with sporadic and 8 patients with familial forms of epithelial ovarian tumors. Evaluation of a set of markers positioned telomeric to BRCA1 on chromosome 17q21 resulted in the highest degree of LOH, 73% (29/40), indicating that a candidate locus involved in ovarian cancer may reside distal to the BRCA1 gene. Russell et al. (2000) isolated the SEPT9 gene, which they designated ovarian/breast (Ov/Br) septin, as a candidate for the ovarian tumor suppressor gene that had been indirectly identified by up to 70% LOH for a marker at chromosome 17q25 in a bank of malignant ovarian tumors. Two splice variants were demonstrated within the 200-kb contig, which differed only at exon 1. The septins are a family of genes involved in cytokinesis and cell cycle control, whose known functions are consistent with the hypothesis that the human 17q25 septin gene may be a candidate for the ovarian tumor suppressor gene. - Chromosome 9p24 By transfection of NIH-3T3 cells with genomic DNA from a human ovarian adenocarcinoma tumor cell line, Halverson et al. (1990) identified a rearranged human DNA sequence that was generated during transfection and induced both morphologic transformation and tumorigenesis. One fragment mapped to human chromosome 9p24 and the other to human chromosome 8. Because rat ovarian surface epithelial cells transformed spontaneously in vitro have been found to have homozygous deletions of the interferon alpha gene (IFNA; 147660) on 9p22, suggesting inactivation of a tumor-suppressor gene in that region may be crucial for the development of ovarian cancer, Chenevix-Trench et al. (1994) used microsatellite markers and Southern analysis to examine the homologous region in humans, 9p, for deletions in sporadic ovarian adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity occurred in 34 (37%) of 91 informative sporadic tumors, including some benign, low-malignant-potential and early-stage tumors, suggesting that it is an early event in the development of ovarian adenocarcinoma. Furthermore, homozygous deletions on 9p were found in 2 of 10 independent cell lines. Deletion mapping of the tumors and cell lines indicated that the candidate suppressor gene inactivated as a consequence lies between D9S171 and the IFNA locus. This region is deleted in several other tumors and contains a melanoma predisposition locus (155601). In a note added in proof, Chenevix-Trench et al. (1994) suggested that the target of these 9p deletions might be CDKN2 (600160) as described by Kamb et al. (1994). MOLECULAR GENETICS - Germline Mutations Stratton et al. (1999) conducted a population-based study to determine the contribution of germline mutations in known candidate genes to epithelial ovarian cancer diagnosed before the age of 30 years. Two of 101 women with invasive ovarian cancer had germline mutations in the MLH1 gene (120436), which is involved in hereditary nonpolyposis colorectal cancer-2 (HNPCC2; 609310). In addition to colon cancer, ovarian cancer may be a manifestation of this syndrome. No germline mutations were identified in any of the other genes analyzed, including BRCA1, the 'ovarian cancer-cluster region' (nucleotides 3139-7069) of BRCA2, and MSH2. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or HNPCC. There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk = 1.6, P = 0.01), but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had an increased risk of ovarian cancer, myeloma, and non-Hodgkin lymphoma. The data indicated that germline mutations in BRCA1, BRCA2, MSH2, and MLH1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Liede et al. (1998) raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, the 185delAG mutation in the BRCA1 gene (113705.0003) segregated with the cancer. Liede et al. (1998) concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. - Somatic Mutations Cesari et al. (2003) identified the complete PARK2 gene (602544) within an LOH region on chromosome 6q25-q27. LOH analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%), both of which are located within the PARK2 gene. Expression of the PARK2 gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, Cesari et al. (2003) found 2 somatic truncating deletions in the PARK2 gene (see, e.g., 602544.0016) in 3 of 20 ovarian cancers. The data suggested that PARK2 may act as a tumor suppressor gene. Because PARK2 maps to FRA6E, one of the most active common fragile sites in the human genome (Smith et al., 1998), it may represent another example of a large tumor suppressor gene, like FHIT (601153) and WWOX (605131), located at a common fragile site. Denison et al. (2003) found that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian tumors were heterozygous for the duplication or deletion of 1 or more exons in the PARK2 gene. Additionally, 3 of 23 (13%) nonovarian tumor-derived cell lines were found to have a duplication or deletion of 1 or more parkin exons. Diminished or absent parkin expression was observed in most of the ovarian cancer cell lines when studies with antibodies were performed. Denison et al. (2003) suggested that parkin may represent a tumor suppressor gene. Sellar et al. (2003) determined that D11S4085 on 11q25 is located in the second intron of the OPCML gene (600632). OPCML was frequently somatically inactivated in epithelial ovarian cancer tissue by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with tumor suppressor gene properties both in vitro and in vivo. A somatic missense mutation from an individual with epithelial ovarian cancer showed clear evidence of loss of function (600632.0001). These findings suggested that OPCML was an excellent candidate for an ovarian cancer tumor suppressor gene located on 11q25. By examining DNA copy number of 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. - Modifier Genes Quaye et al. (2009) used microcell-mediated chromosome transfer approach and expression microarray analysis to identify candidate genes that were associated with neoplastic suppression in ovarian cancer cell lines. In over 1,600 ovarian cancer patients from 3 European population-based studies, they genotyped 68 tagging SNPs from 9 candidate genes and found a significant association between survival and 2 tagging SNPs in the RBBP8 gene (604124), dbSNP rs4474794 (hazard ratio, 0.85; 95% CI, 0.75-0.95; p = 0.007) and dbSNP rs9304261 (hazard ratio, 0.83; 95% CI, 0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging SNPs in 314 ovarian tumors identified associations between somatic gene deletions and survival. Thirty-five percent of tumors in 101 informative cases showed LOH for the RBBP8 gene, which was associated with a significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p = 0.001). Quaye et al. (2009) concluded that germline genetic variation and somatic alterations of the RBBP8 gene in tumors are associated with survival in ovarian cancer patients. CLINICAL MANAGEMENT Chien et al. (2006) studied HTRA1 (PRSS11; 602194) expression in tumors from 60 patients with epithelial ovarian cancer and 51 with gastric cancer (137215) and found that those with tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. Chien et al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. PATHOGENESIS Using a PCR-based differential display method, Mok et al. (1994) identified a gene, termed DOC2 (601236), that was expressed in normal ovarian epithelial cells, but downregulated or absent from ovarian carcinoma cell lines. The DOC2 gene maps to chromosome 5p13. Mok et al. (1998) reported that transfection of the DOC2 gene into an ovarian carcinoma cell line resulted in significantly reduced growth rate and ability to form tumors in nude mice. Among 48 primary ovarian cancer tumors and corresponding metastases, Blechschmidt et al. (2008) found a significant association (p = 0.008) between reduced E-cadherin (CDH1) expression in the primary cancer tissue and shorter overall survival. Patients with decreased E-cadherin expression and increased SNAIL (SNAI1; 604238) expression in the primary tumor showed a higher risk of death (p = 0.002). There was no significant difference in expression of E-cadherin or SNAIL between primary tumors and metastases. The findings were consistent with a role for E-cadherin and SNAIL in the behavior of metastatic cancer. Merritt et al. (2008) observed decreased mRNA and protein expression of the RNAse III enzymes DICER1 (606241) and DROSHA (RNASEN; 608828) in 60 and 51%, respectively, of 111 invasive epithelial ovarian cancer specimens. Low DICER1 expression was significantly associated with advanced tumor stage (p = 0.007), and low DROSHA expression with suboptimal surgical cytoreduction (p = 0.02). Cancer specimens with both high DICER1 expression and high DROSHA expression were associated with increased median survival (greater than 11 years vs 2.66 years for other subgroups; p less than 0.001). Statistical analysis revealed 3 independent predictors of reduced disease-specific survival: low DICER1 expression (hazard ratio, 2.10; p = 0.02), high-grade histologic features (hazard ratio, 2.46; p = 0.03), and poor response to chemotherapy (hazard ratio, 3.95; p less than 0.001). Poor clinical outcomes among patients with low DICER1 expression were validated in an additional cohort of patients. Although rare missense variants were found in both genes, the presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low DICER1 expression. The findings implicated a component of the RNA-interference machinery, which regulates gene expression, in the pathogenesis of ovarian cancer. Merritt et al. (2009) noted that 109 of the 111 samples used in the 2008 study had serous histologic features, of which 93 were high-grade and 16 low-grade tumors. To explore the genetic origin of ovarian clear cell carcinoma, Jones et al. (2010) determined the exomic sequences of 8 tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, Jones et al. (2010) identified 4 genes that were mutated in at least 2 tumors. PIK3CA (171834), which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS (190070), which encodes a well-known oncoprotein, had previously been implicated in ovarian clear cell carcinoma. The other 2 mutated genes were previously unknown to be involved in ovarian clear cell carcinoma: PPP2R1A (605983) encodes a regulatory subunit of serine/threonine phosphatase-2, and ARID1A (603024) encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggested that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 ovarian clear cell carcinomas, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. Jones et al. (2010) concluded that their results suggested that aberrant chromatin remodeling contributes to the pathogenesis of ovarian clear cell carcinoma. GENOTYPE/PHENOTYPE CORRELATIONS Grindedal et al. (2010) performed a retrospective survival study of 144 women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had a mutation in MSH6. The mean age of onset was 44.7 years, compared to 51.2 years in carriers of BRCA1 (113705) mutations with ovarian cancer and 57.5 in carriers of BRCA2 (600185) mutations with ovarian cancer (Risch et al., 2001). Most (81.5%) women with MMR mutations were diagnosed at stage 1 or 2. Twenty-nine (20.1%) of 144 woman with MMR-related ovarian cancer died of their ovarian cancer. The 5-, 10-, 20- and 30-year survival specific for deaths due to ovarian cancers were 82.7%, 80.6%, 78.0% and 71.5%, respectively. About 50% of the women developed another cancer in the HNPCC/Lynch syndrome tumor spectrum. The 5-, 10-, 20-, and 30-year survival specific for deaths due to HNPCC/Lynch syndrome-associated cancers were 79.2%, 75.7%, 68.4% and 47.3%, respectively. Overall, the survival for women with ovarian cancer due to MMR mutations was better than for those with ovarian cancer due to BRCA1/2 mutations, which is less than 40% at 10 years. The lifetime risk of ovarian cancer in MMR mutation carriers was about 10% and the risk of dying from ovarian cancer was 20%, yielding an overall risk of dying from ovarian cancer of about 2% in MMR mutation carriers. Grindedal et al. (2010) suggested that mutations in the MMR and BRCA1/2 genes may predispose to biologically different types of tumors. ANIMAL MODEL Dinulescu et al. (2005) developed a mouse model of ovarian cancer. A recombinant adenoviral vector expressing an oncogenic Kras (190070) allele within the ovarian surface epithelium resulted in the development of benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma; 7 of 15 mice (47%) also developed peritoneal endometriosis (131200). When the Kras mutation was combined with conditional deletion of Pten (601728), all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary. ► ▼ PROSTATE CANCER, HEREDITARY, 13; HPC13 611928 only shown in mice A number sign (#) is used with this entry because single-nucleotide variation in the promoter region of the MSMB gene (157145) has been associated with the development of prostate cancer. For a general discussion of hereditary prostate cancer, see 176807. MAPPING In a large 2-stage genomewide association study of prostate cancer, Thomas et al. (2008) identified a SNP dbSNP rs10993994 (157145.0001) in the proximal promoter of the MSMB gene on chromosome 10q11.2 that was significantly associated with prostate cancer risk (7.31 x 10(-13)). The MSMB gene encodes beta-microseminoprotein (MSP), a member of the immunoglobulin binding factor family synthesized by epithelial cells of the prostate and secreted into seminal plasma. MSP and its binding protein in serum, PSPBP (PI16), have been proposed as serum markers for early detection of high grade prostate cancer. Although its expression has been noted in both normal and neoplastic prostate tissue, MSMB can be silenced by EZH2 (601573) in advanced, androgen-insensitive prostate cancer. Buckland et al. (2005) found that the dbSNP rs10993994 SNP of MSMB functionally altered in vitro gene expression. Eeles et al. (2008) conducted a genomewide association study using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA; see 176820) concentration (less than 0.5 ng/ml). Analysis of these samples for 541,129 SNPs was performed using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. Eeles et al. (2008) identified a SNP in the MSMB gene, dbSNP rs10993994, that was significantly associated with prostate cancer (8.7 x 10(-29)). The SNP dbSNP rs10993994 is 2 basepairs upstream of the transcription start site of MSMB. The risk allele, T, affects multiple predicted binding sites for transcription and splicing factors. Putative androgen and estrogen binding sites lie less than 50 kb upstream from this SNP. Loss of expression of MSMB is associated with recurrence after radical prostatectomy (Reeves et al., 2006). By fine-mapping analysis of a 65-kb region on chromosome 10q including dbSNP rs10993994 in 6,118 prostate cancer cases and 6,105 controls of European origin, Lou et al. (2009) found dbSNP rs10993994 remained the SNP most strongly associated with prostate cancer risk (p = 8.8 x 10(-18); heterozygous odds ratio (OR) of 1.20, homozygous OR of 1.64). Lou et al. (2009) stated that the SNP was located at position -57. In vitro functional analysis showed that the T allele was associated with decreased transcriptional activity and that the C allele preferentially bound to the CREB transcription factor (123810). Analysis of tumor cell lines with a CC or CT genotype revealed a higher level of MSMB gene expression compared to cell lines with a TT genotype. Lou et al. (2009) suggested that regulation of MSMB expression is a plausible mechanism accounting for the association with prostate cancer identified at this locus. Yeager et al. (2009) sequenced a 97-kb region of chromosome 10q11.2 including the area surrounding the MSMB gene and the NCOA4 gene (601984) in 70 unrelated individuals, including 36 with prostate cancer. They identified a 51-kb block of linkage disequilibrium (LD) containing dbSNP rs10993994 and the proximal promoter of the MSMB gene. No additional variants in LD with dbSNP rs10993994 were identified, suggesting that this is the probable variant that accounts for the association with prostate cancer. In total, 241 novel polymorphisms were identified in the 97-kb region, but none were in the exons of the MSMB gene. No polymorphic sites were found in the first 6 exons of the NCOA4 gene, but several were observed in exons 7 through 10. GeneRIFs: ► ▼ dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma Modulation of signal transducer and activator of transcription 3 activities by p53 tumor suppressor in breast cancer cells. Cytokine signaling: STATS in plasma membrane rafts actdivated by fiboblst growth factor 3 and adapter protein SH-B Stat1 and Stat3 may support cell growth in part via c-myc gene activation in primary erythroleukemia cells. inhibits gamma-globin gene expression in erythroid cells. Breast Carcinoma cell growth could be inhibited by dominant-negative versions of STAT3. STAT3 isoforms are differentially expressed and phosphorylated during progression of granulocytic differentiation. The C-terminal domain of Stat3 negatively regulates its receptor binding activity only in the absence of the first alpha-helix of the coiled-coil domain, which leads to a hypothesis of intramolecular interaction. The transforming capacity of constitutively activated STAT3 and STAT5 mutants strongly supports their fundamental role in the process of malignant transformation in hematopoietic cells IL-6-inducible expression of the hAGT promoter is mediated by physical association of the COOH terminus of STAT3 with p300/CBP, the recruitment of which targets histone acetylation and results in chromatin remodeling. STAT5b-RARalpha and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway. Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet-activating factor, JAK-2, and Src in human umbilical vein endothelial cells Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis Stat3 activity is significantly increased in both prostate cancer and adjacent normal prostate tissue; activation may be an early event in prostatic epithelial carcinogenesis Stat3 and GRP58 were observed to be coassociated with cytoplasmic membranes activated in human ovaarian carcinoma; co-expressed with oncostatin M and its receptor Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c STAT3 is activated by HGF/HGFR and has a role in fetal organogenesis and placental tissue constitutive STAT3 activation contributes to tumor growth in SCCHN, independent of the EGFR autocrine axis. Data show that IL-6/raft/STAT3 signaling is a chaperoned pathway that involves caveolin-1 and HSP90 as accessory proteins and suggest a mechanism for the preservation of this signaling during fever. The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through its dephosphorylation. PKC delta associates with IL6ST via Stat3 and enhances Stat3-gp130 interaction Platelet signaling pathways activated by thrombopoietin may affect mitochondrial transcription via activation of mitochondrial STAT3 findings suggest that activated STAT3 signaling directly contributes to malignant progression of primary effusion lymphoma by preventing apoptosis, acting through the prosurvival protein survivin selectively activated in immature dendritic cells by expression of HIV nef Schwannomin and HRS inhibit Stat3 activation in schwannoma cells. ablation of Stat3 function converts EGF from a growth/survival factor for RA synoviocytes to a death factor Inhibition suppresses proliferation and induces apoptosis in glioblastoma multiforme cells Dysregulated STAT3 activity by PML/RAR alpha may participate in the pathogenesis of APL. Kaposi sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through inhibition of this protein. Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer expression and DNA-binding activity of this protein in alcoholic cirrhosis compared to normal liver and primary biliary cirrhosis in humans identification of tip60 as a co-repressor for STAT3 inhibition by differentiation-inducing factor-1 is involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway This protein is activated by leptin which activates the FAAH promoter in T cells. Ataxia telangiectasia mutated proteins, MAPKs, and RSK2 are involved in the phosphorylation of this protein. THE presence of this protein and its phosphorylated derivative in node-negative breast cancer shows nuclear localization is associated with a better prognosis. independent and cooperative activation of chromosomal c-fos promoter by STAT3 STAT3 is constitutively activated in Crohn's patients but not in healthy volunteers Hematopoietic CD34+ cells secreted IL-15 that, through autocrine/paracrine loop distinct signal pathways, activated NF-kB in bone marrow and cord blood progenitors, and activated STAT3 and STAT5 in peripheral G-CSF-mobilized and BM progenitors only. GRIM-19 protein specifically suppresses Stat3 protein activity via functional interaction. gp120 induces activation of STAT1, STAT3, and STAT5 in CD4+ cells of lymphocyte or monocyte/macrophage lineages. We conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway. activation of STAT3 was dependent on Ser727 phosphorylation, in the absence of detectable Tyr705 phosphorylation; expression of human STAT3 in murine macrophages rescued inhibition of human Mcl-1 promoter gene activation and cell death induced by NaSal RET/PTC associates with STAT3 and activates it by the specific phosphorylation of the tyrosine 705 residue. STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes. Inhibition of this protein with a decoy oligodeoxyribonucleotide abolishes head and neck cancer cell growth. G protein-coupled receptors activate STAT3 via G alpha(16), a G alpha subunit which is primarily expressed in hematopoietic cells. Analysis of this protein's pathway in myeloma: its activation and cyclin D1 dysregulation are mutually exclusive. ubiquitylation and degradation by mumps virus V protein prevents responses to interleukin-6 and v-Src signals and can induce apoptosis in STAT3-dependent multiple myeloma cells and transformed murine fibroblasts Results provide evidence that interleukin-13 induces p38 MAP kinase phosphorylation and activation, which regulates Stat1 and Stat3 serine 727 phosphorylation. Data suggest there is no defect in the JAK/STAT pathway in the tested melanoma cell lines, and that interferon resistance must be mediated through other components. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. We now demonstrate ligand-independent activation of Stat3 by high cell density in multiple cancer cell lines.Interference with cdk2 activity upregulates Stat3 phosphorylation and Stat3-directed DNA-binding activity. AR and PIAS3 regulate the STAT3-mediated transcriptional activity by their physical protein-protein competition on STAT3 STAT3 has a role in the pathogenesis of human chronic myelogenous leukemia Stat1 and Stat3 exist as stable homodimers prior to activation Stat3 has a role in transducing survival signals downstream of tyrosine kinases such as Src, EGF-R, and c-Met, as well as cytokines such as IL-6, in human nonsmall cell lung cancers STAT1 and STAT3 may, at least in part, mediate angiotensin II-induced TIMP-1 mRNA expression in human renal proximal tubular epithelial cells, implicating a role of the STAT signaling pathway in pathogenesis of renal tubulointerstitial fibrosis. STAT3 activation associated with better disease-free survival in nasopharyngeal carcinoma STAT3 activation is required for keratinocyte differentiation in normal human stratified squamous epithelium Stat3 is transactivated via IL-6 response elements on fibrinogen promoters with participation of additional transcription factors Nef activates STAT3 through a mechanism mediated by the release of soluble factor(s) in human monocyte derived macrophages. Differentiation-dependent expression of STAT3 may modify responses to growth factors in the cancers of the head and neck. The activation of signal transducer and activator of transcription 3 (Stat3) is obligatory for the survival of INA-6 multiple myeloma cells. Signal transducer and activator of transcription 3 is the most potent activator of acute-phase gene transcription. STAT3 is stimulated by Galpha16 via a c-Src/JAK- and ERK-dependent mechanism STAT3/NF-kappaB p65 cross-talk activated by IL-1 via TRAF6. role in regulating expression of hepatocyte growth factor Specific DNA binding activity of two STAT3 variants (STAT3alpha and beta) was observed in immature trophoblasts and appeared to be lost in term placentae. The malignant phenotype of choriocarcinoma cells coincides with a high degree of STAT3 activity. Although the data show that STAT3 is required for the majority of IL-10 functions, there are elements of the anti-inflammatory activity of IL-10 that are STAT3 independent. STAT3 recombinant fusion protein shuttles continuously between the cytosol and the nucleus in unstimulated cells interaction of Stat3 and ZBP-89 may be crucial for overcoming the effects of the repressor ZBP-89, which suggests a novel mode for Stat3 gene activation. In the luciferase assay, ATBF1 was found to have no influence on STAT3 signaling induced by IL-6 stimulation, but it did synergistically enhance PIAS3 inhibition of activated STAT3. Taken together, our findings demonstrate that constitutively activated Stat3 up-regulates HSP27 and may facilitate phosphorylation of HSP27 at serine residue 78. G-CSF like IL-10 inhibits LPS-induced TNF-alpha production in human monocytes through selective activation of STAT3 and the immunomodulation observed in vivo by G-CSF administration may be partly ascribed to the direct effect of G-CSF on monocyte function MITF and STAT3 cooperatively induce c-fos, resulting in cellular transformation STST3 activation is mediated by EGFR and c-Src and facilitated by Pyk2 interactions of the phosphotyrosine ligands with specific amino acid residues of Stat3 SH2 region are described Stat3 activity is upregulated during the confluence-mediated growth arrest by a signalling mechanism that requires JAKs IL-10 gene regulation in colon tumor cells is mediated by STAT3, which is phosphorylated after the binding of IL-6 the IL-6 receptor. N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) from P. aeruginosa ablates STAT3 activity in breast tumor cells. cells from multiple myeloma patients express constitutively active NF-kappaB and STAT3, and suppression of these transcription factors inhibits the survival of the cells STAT3 signaling supports gastric cancer cell survival in association with survivin expression. a profound in vivo activation of STAT3 is observed in mycosis fungoides (MF) tumors but not in the early stages of MF. STAT3 protects tumor cells from apoptosis in vitro. Taken together, these findings suggest that STAT3 is a malignancy factor in CTCL. the c-src kinase/STAT3 pathway has a role in Ox-PAPC-mediated IL-8 expression in endothelial cells STAT3gamma is rapidly generated from STAT3alpha by limited proteolysis with granule-derived serine proteases during preparation of neutrophil lysates Inhibition of STAT3 reduced the motility of ovarian cancer cells in vitro, and activated STAT3 localized not only to nuclei but also to focal adhesions in these cells. STAT3 directly contributes to the high level of TIMP1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Constitutive activation of Stat3 may play an important role in the tumorigenesis of colorectal carcinoma results show STP-A11 (Saimiri transforming protein oncogne of Herpesvirus saimiri subgroup A strain 11) independently targets two important cellular signaling molecules, Src and Stat3; these proteins cooperate to induce STP-A11-mediated transformation expression of STAT-3 induced by Epstein-Barr virus (EBV) LMP-1 (latent membrane protein) and may be part of the viral programming that regulates viral latency and cellular transformation constitutive activation of Akt and NFkappaB, but not Stat3, contributes significantly to the progression of diffuse gliomas importance of STAT3 signaling in the regulation of neuronal growth and differentiation by the mu-opioid receptor. Although the methylation frequency of SOCS-1 is low, the data of Fujitake et al. indicate role of JAK/STAT/SOCS pathway in gastrointestinal tumorigenesis. We found that the amino terminal domain of STP A11 is required for both STAT3 interaction and activation, and that physical interaction is required for STAT3 activation. STAT3 interacts with STRA13 and modulates transcription of STAT3-dependent targets. Inhibition of Stat3 activity by TEL represents a novel mechanism regulating the Stat3 signaling pathway Stat3 mediated by c-Met is frequently associated with the progression of oral squamous cell carcinoma Existence of a factor in mouse feeder layer cells that acts to maintain huma embyonic stem cells cell renewal in a STAT3-independent manner. data reveal an important role for MgcRacGAP in STAT3 activation, and demonstrate that MgcRacGAP regulates IL-6-induced cellular differentiation in which STAT3 plays a pivotal role Promotes the initiation of transcription but also regulates chromatin remodeling and transcription elongation through its interaction with BRG1 and cdk9. Detailed pathway analysis revealed that BM stromal cells stimulate STAT3 via the IL-6R, and MEK1/ERK1 pathways, via IL-6R-independent mechanisms STAT3 forms a related complex in cells upon oxidative stress. interacting at cysteine 259. constitutively active Stat3 upregulates MEK5 in the breast epithelial cells. MEK5 may be one of the Stat3-regulated genes and plays its essential roles in oncogenesis STAT3 activation is capable of initiating intracellular antiviral pathways Growth hormone attenuates the transcriptional activity of Runx2 by facilitating its physical association with Stat3beta Ectopic expression of wild-type but not Thr(p+1loop)-->Met substituted EPH family members constitutively phosphorylated STAT3 The conserved STAT3 region from 752 to 761, called STAT3 CR2, plays critical roles in STAT3-dependent transcription by recruiting SRC-1 and allowing Ser727 phosphorylation. Cold ischemia and reperfusion induced increased levels in liver transplantation. The STAT3 was detected in cytoplasm and nucleus and in carcinomas it was limited to cytoplasm. Coordination between Stat1 & Stat3 activation determines GTPCH I induction. Stat1 & NF-B activation, coordinated with the lack of Stat3 activation, accounts for cytokine-stimulated GTPCH I induction in endothelial cells. The N-terminal part of the 1st intracellular loop (ICL) is needed to activate Jak2 after SDF-1alpha binding to CXCR4, leading to phosphorylation of only one cytoplasmic Tyr, present at the C terminus of the 2nd (ICL), which triggers STAT3 activation. suppressor of cytokine signaling 3 regulates Hepatocyte growth factor-induced keratinocyte migration by inhibiting STAT3 phosphorylation an increased transcriptional level of constitutive STAT3 may be related to the suppressive regulation of the apoptotic pathway in intrinsically chemo-resistant NSCLC cells. acetylation of Stat3 can stimulate its sequence-specific DNA binding ability and transactivation activity. Lys685 acetylation critical for Stat3 to form dimers required for cytokine-stimulated DNA binding & transcriptional regulation, to enhance transcription of cell growth-related genes & to promote cell cycle progression after treatment with oncostatin M one of the major roles of Stat3 in the G-CSF signaling pathway is to augment the function of C/EBPalpha, which is essential for myeloid differentiation TFF3 and the essential tumor angiogenesis regulator VEGF(165) exert potent proinvasive activity through STAT3 signaling in human colorectal cancer cells. Results indicate that SOCS-7 is a dysregulator of prolactin, leptin, and growth hormone signaling and that its mode of action is a variation of SOCS protein inhibition of cytokine-inducible STAT3 and 5-mediated signal transduction. Over-expression of VEGF may be correlated with elevated STAT3 activation in parental cell line IL-6-induced STAT3 activation in human prostate cancer cell lines. HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE regulate Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas pharmacological agents that can selectively reduce the P-STAT3 levels in human cancer cells result in tumor apoptosis and growth inhibition previously uncharacterized genes induced by Stat3 implicated in signaling pathways common to both wound healing and cancer including cell invasion and migration, angiogenesis, modulation of coagulation, and repression of interferon-inducible genes Findings provide evidence that STAT 3 signal activity in head and neck carcinomas, which is partially responsible for proliferative activity, can be controlled via the EGFR. STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases extracellular signal-dependent nuclear transport of STAT3 is mediated by various importin alphas, importin beta, and Ran demonstrate using RNAi that Stat3 activation is necessary in the invasive phenotype of trophoblast cells and can be controlled via Leukemia Inhibitory Factor (LIF) cIAP2 expression is up-regulated by IFN-alpha and IFN-gamma through the JAK2-STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN-alpha- and IFN-gamma-mediated antiapoptotic effect on human neutrophils. STAT3 may transform cells by inducing epigenetic silencing of SHP-1 in cooperation with DNMT1 and histone deacetylase 1 interacts with dengue-2 virus NS1 protein activation by leptin is associated with gastric cancer cell proliferation STAT3 signaling pathway is involved in IL-6-induced neuroendocrine(NE) differentiation and that p38 MAPK is associated with IL-6-stimulated growth regulation in NSCLC-NE cells. The physiological role of Stat3 in anaplastic large cell lymphomas and the effects of inhibition of expression of the gene on tumorigenesis is reported. Activation of Stat3 signaling in respiratory epithelial cells of STAT3 transgenic mice protects against hyperoxia-induced inflammation and injury in the lung. STAT3 signaling is important in the pathogenesis of classical Hodgkin lymphoma Stat3 is an important component of a pathway emanating from tumor antigen of Simian Virus and leading to neoplastic conversion Data show that medroxyprogesterone acetate treatment of mammary tumor cells up-regulated Stat3 protein expression and induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation. Observational study of gene-disease association. (HuGE Navigator) Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV1 in both adults and children with asthma. These suggest that JNK and STAT3 may constitute a universal signaling pathway to mediate adiponectin's pathophysiological effects on metabolic syndrome and cancer. Janus kinase Tyk2 and the transcription factor Stat3 serve as downstream components in the signaling cascade resulting in upregulation of C5aR expression STAT3 physically interacts with epidermal growth factor receptor in the nucleus, leading to transcriptional activation of inducible nitric oxide synthase. Results identify a cohort of STAT3 targets that may mediate its role in oncogenesis in breast and prostate cancer. results demonstrate for the first time that prostacyclin receptor activation by cicaprost can lead to STAT1 and STAT3 phosphorylations via signaling pathways involving pertussis toxin-insensitive G proteins, ERK and JNK Stat3 is required for both basal and growth signal-induced expression of HIF-1 STAT3 has a role in colorectal tumor growth Growth factors and cytokines stimulate hTERT expression in primary human cells in a STAT3-dependent manner. STAT3 is a key regulator of hTERT expression in both normal and tumor cells. Association between STAT3 and ARHI as well as the functional inhibition of STAT3 transcriptional activity by ARHI suggests a novel mechanism through which a putative tumor suppressor gene can inhibit STAT3 activity in breast and ovarian cancers. constitutive Stat3 signaling may be one of the key upstream regulators to induce downstream proteins which may play important roles in Stat3-mediated oncogenesis in breast cancer STAT3 can participate in neoplastic transformation through novel and non-canonical mechanisms [review] End-stage hepatitis c and alcoholic liver cirrhosis is characterized by impaired Stat3 DNA-binding possibly through up-regulation of Pias3. repression of tumor protein p53 expression by Stat3 is likely to have an important role in development of tumors Results suggest a connection between leukemia inhibitory factor-driven STAT3 activity and invasiveness of choriocarcinoma and trophoblast cells. These data demonstrate that Arg-214/215 are involved in CRM1-mediated STAT3 nuclear export and the regulation of STAT3 activity. NF-kappaB and STAT3 are activated by proteolysis inducing factor in human Kupffer cells and monocytes Inhibition of STAT3 signaling in colon carcinoma tumors and cell lines induces apoptosis and cell cycle arrest of colon carcinoma cells. Study proved that overexpression of STAT3(WT) could augment the migration of BEL-7402 cells, while STAT3(CYF) could decrease the migration. We provide evidence that STAT3 plays an essential role in cytokine-driven SAA expression, although the human SAA gene shows no typical STAT3 response element Cyclooxygenase-2-dependent activation of STAT3 by interleukin-6 has a role in non-small cell lung cancer acetylation-deacetylation reaction as a novel signaling mechanism controlling the IL-6-STAT3 pathway in the hepatic acute phase response STAT3-mediated transcriptional activation in inhibited by Daxx Stat3 downregulation in vSrc transformed NIH3T3 cells or in breast cancer lines with activated Src induces apoptosis, but in normal cells Stat3 inhibition at post-confluence causes apoptosis while in sparsely growing cells it induces growth retardation STAT3 and PY-STAT3 in the cytoplasm have roles in endocytosis Our results suggest that p-ser727-STAT3 may be involved in the pathogenesis of breast cancer in an ER-dependent manner. SOCS-1 methylation status can differentially affect STAT3 activation This review of head and neck squamous cell carcinoma discusses how STAT3 alters the tumor cell cycle, prevents apoptosis, and mediates proliferation and survival of tumor cells. findings demonstrate that Stat3 plays a critical role in the tumorigenesis, but not in the cell survival, of cutaneous squamous cell carcinoma cells and suggest that additional pro-apoptotic signals are necessary for the induction of apoptosis there are tissue-specific differences in IL-6-receptor-gp130-coupled signaling which limit the extent of Stat3 activation and gammaFBG expression during lung inflammation Tax-mediated regulations of IL-6R and sIL-6R observed in HTLV-I-associated disorders may contribute to proliferation of HTLV-I-infected T cells through activation of inducible STAT3 Activation requires the catalytic activity of Brk. changes in the relative expression and activation of STAT1 and STAT3 that occur during immune responses determine the nature of cellular responses to type I IFNs Stat3 is involved in keloid pathogenesis. Inhibitors of Stat3 may be useful therapeutic strategies for the prospective treatment of keloid scars. Stat3 undergoes proteolytic processing by caspases that reduces its expression and leads to the formation of cleavage fragments that may modulate Stat3 transcriptional activity Stat3-mediated p100 processing to p52 requires activation of Stat3 by the acetyltransferase activity of cAMP-response element-binding protein (CREB)-binding protein (CBP)/p300 To our knowledge, this is the first study on the poor prognosis of p-STAT3 in human colorectal adenocarcinomas. These findings suggest that expression of p-STAT3 is related to tumour invasion and poor prognosis of human colorectal adenocarcinoma. role for IL-11 via pSTAT3 and SOCS3 in initiating and progressing decidualization Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6 Haplotypes of STAT3 predict cardiovascular disease in renal dialysis patients. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. Atiprimod blocked Stat3 activation and inhibited colony-forming cell proliferation in acute myeloid leukemia cells. Mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation. IL-6 induces Protein S expression via STAT3. Possible function for IL-6-induced Protein S expression in cell survival. STAT3 activation by IL-6 provides an antiapoptotic advantage in human cord blood cells CD34+ cells, essentially owing to the expression of bcl-2. STAT3 binds in vitro to 2 STAT3 SIE/GAS-binding sites identified in promoter 1 and enhancer 1 of the DNMT1 gene mutant JAK2 contributes to myelofibrosis with myeloid metaplasia pathogenesis by constitutively phosphorylating STAT3 and diminishing myeloid cell apoptosis These reuslts show a significant association between the expression of the phosphorylated/active form of STAT3 (pSTAT3) and that of TIMP1. Stat3 binding at position -1024 of the endothelial nitric-oxide synthase (eNOS) promoter mediates Stat3 inhibition of eNOS promoter activity. Phosphorylation in trophoblasts or blood mononuclear cells activated with lipopolysaccharide or phytohemagglutinins showed phosphorylation of this protein. PDTC downregulates IL-6-induced STAT3 activation by altering the stability of STAT3-Hsp90 complex observed a reperfusion time-dependent increase in the tyrosine phosphorylation of STAT1 and STAT3 at residues 701 and 705, respectively, which was dramatically reduced by tempol STAT3 is a key effector of baseline hepcidin expression and during inflammatory conditions. results suggest that phospho-Stat3 expression might be associated with angiogenesis, anti-apoptosis, and tumor progression in gastric cancer The activated (phosphorylated) Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. The interruption of Stat3 signaling could reverse resistance to paclitaxel and perhaps other chemotherapy agents in human cancer. These results suggest a relevant role for STAT5 and Bcl-xL as apoptosis-regulatory proteins in the pathogenesis of lung cancer, and overexpression of both Neu and activated STAT3, could be related with the proliferation rate in lung carcinoma cells. there is a cross-talk between the NFkappaB and the STAT3 signaling systems, and HNSCC may result from the aberrant activity of a signaling network STAT3 activation by G alpha(s) distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase The Ras/Raf-1/MEK1/ERK cascade culminates in nicotine up-regulated expression of the gene encoding STAT-3, whereas recruitment and activation of tyrosine kinase JAK-2 phosphorylates it. To determine the prosurvival function of STAT3 vs STAT5 within the same tumor model, genes were profiled in STAT3- or STAT5-depleted human lymphoblastic lymphoma-derived cell line YT cells by apoptosis-specific microarrays Chromium activates epithelial cell Lck to signal for prolonged STAT3 activation and transactivation of interleukin-6, an important immunomodulator of lung disease progression Leptin and TGF-beta1 synergistically augmented activation of signalling components of mitogen-activated protein kinase (MAPK), STAT3 and Smad but did not modulate the expression of LEPR-B. The STAT3 pathway is involved in Cdk5-dependent proliferation of medullary thyroid cancer cells through Ser-727 phosphrylation. Activated STAT3 translocates to the nucleus of KSHV-infected endothelial cells, where it can bind to STAT3-specific DNA elements and can activate STAT3-dependent promoter activity. BRG1 is constitutively present at IL-6-responsive promoters and is required for STAT3 recruitment, downstream histone modifications, and IL-6-induced chromatin remodeling. STAT3 activity can suppress both IL-6 and tumor necrosis factor production in lipopolysaccharide-stimulated macrophages. activation of STAT3 may play an important role in the tumorigenesis of gastric adenocarcinoma These data suggest that STAT3 signaling is an important common element and may contribute to the remodeling and adaptation of skeletal muscle following resistance exercise. tumor samples from FMTC patients showed strong nuclear staining of phosphorylated ERK1/2 and Ser(727) STAT3; FMTC-RET mutants activate a Ras/ERK1/2/STAT3 Ser(727) pathway, which plays an important role in cell mitogenicity and transformation. let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes The expression of STAT3 was positively related to that of Survivin and Ki67 in in nasal NK/T cell lymphoma. SOCS-3 epigenetic silencing is responsible for sustained IL-6/STAT-3 signaling and enhanced Mcl-1 expression in cholangiocarcinoma Cell confluence-induced Stat3 signaling is induced in Madin-Darby canine kidney epithelial cells in triggering dome formation through sodium hydrogen exchanger-3 augmentation. Myocardial STAT3 protein levels are reduced and serum levels of activated cathepsin D and 16 kDa prolactin are elevated in postpartum cardiomyopathy patients. Stat3 is activated in human endometrial and cervical cancers and the inhibition of constitutive Stat3 signaling may be an effective target for cancer intervention in these two cancers. In chronic hepatitis C, liver fibrosis progression is characterized by a continuous decline in Stat3 DNA-binding activity related to overexpression and progressive interaction of Pias3-Stat3. STAT-3 activation by DFMO is at least in part mediated through the PKA pathway This review article discusses the role of STAT3 in cancer in detail as evidenced by its constitutive activity in tumor cells, and its regulation of genes that mediate proliferation, suppress apoptosis or promote angiogenesis. silibinin inhibits constitutively active Stat3 and induces apoptosis in DU145 cells, and thus might have potential significance in therapeutic intervention of this deadly malignancy. CYCLIN D1 may be a target gene for leptin mediated growth stimulation of breast cancer cells and molecular mechanisms involve activated Stat3 STAT3 is a substrate of receptor protein tyrosine phosphatase T Increasing the protein levels of the signal transducer and activator of transcription 3 (Stat3) led to Stat3-androgen receptor (AR) complex formation in response to epidermal growth factor (EGF) and interleukin-6 (IL-6) stimulation. found 3 specific patterns of pSTAT-3 and pSTAT-5 expression: uniformly increased pSTAT-3 and pSTAT-5 expression in PV, increased pSTAT-3 and reduced pSTAT-5 expression in ET, and uniformly reduced pSTAT-3 and pSTAT-5 expression in IM. CCL2 mediates fibroblast survival by inhibiting apoptosis through IL-6/STAT3 signaling IL-10 induces IL-10 in monocyte-derived macrophages in an autocrine manner via activation of the transcription factor Stat3. Constitutively activated STAT3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through ITGB6. STAT3 was overexpressed in laryngeal carcinoma. Activation of STAT3 was significantly related to the clinical stage and lymph node metastasis. Activation of the STAT3 signaling pathway plays an important role in the progression of pancreatic cancer, and silencing of the STAT3 gene with RNAi may be a useful anti-invasive therapeutic option in pancreatic cancer. Aberrant activity of STAT3 in colorectal neoplasms is linked to malignant tumor progression through upregulated expression of matrix metalloproteinases MMP-1, -3, -7, and -9. antitumor activity of S3I-201 is mediated in part through inhibition of aberrant Stat3 activation administration of IL-6 could activate receptor gp80/gp130 signaling pathways including downstream extracellular signal-regulated kinase 1/2 and STAT3 phosphorylation in EPCs. STAT3 and PKC differentially regulate telomerase activity during megakaryocytic differentiation of K562 cells. Blockade of the gp130 receptor or sequestration of the interleukin-6 (IL-6) ligand led to a decrease of phosphorylated Stat3 levels in breast cancer. GM-CSF-stimulated CD34(+) cell proliferation is regulated by the JAK/STAT3/survivin signaling pathway. in addition to activating NF-kappaB/p52, LIGHT also activates Stat3 through the NIK pathway These results indicate that expression of the gamma-fibrinogen gene is mainly controlled by the strength of late phase STAT3 activation, which in turn is negatively regulated by the extent of interleukin-1beta-mediated NF-kappaB activity. Stat3 has a role in the photodynamic reaction in cells and tumors The activation of MMP-9 promoter is dependent upon interactions of Fra-1/c-Jun with Stat3. Statistically analyzed distributions of the proteins reflected functional dependences among STAT3, HIF-1alpha, EPO and EPOR in cellular signal conduction. Observational study of gene-environment interaction and pharmacogenomic / toxicogenomic. (HuGE Navigator) STAT3 polymorphism has a role in patient resopnse to IFN-alpha therapy in patients with metastatic renal cell carcinoma These observations suggest that SOCS6 is composed of at least two functional domains required for its biological role in localizing and degrading Stat3 in the nucleus. GRIM-19 suppresses constitutive STAT3-induced cellular transformation in vitro and in vivo by down-regulating the expression of a number of cellular genes involved in cell proliferation and apoptosis The high expression of STAT3 and the low expression of GRIM-19 co-exist in colorectal carcinoma, and may be related to malignant transformation and abnormal proliferation of cells. Since STAT3 reactivation occurred in 14 of 15 solid tumor cell lines, dasatinib combined with Janus-activated kinase inhibitors may have widespread application in cancer treatment. Amino acid residues required for physical and cooperative transcriptional interaction of STAT3 and AP-1 proteins c-Jun and c-Fos. Single nucleotide polymorphism variations are not indicative of obesity and insulin resistnce. In actinic cheilitis, STAT-3 expression depends on the degree of dysplasia, and STAT-3 activation is dysregulated compared with normal tissue Response rates to HCV-specific treatment are higher in HCV/HIV-positive patients carrying the IL-6 HP genotype, which might be because of IL-6 mediated STAT3 activation. Data provide direct evidence for IL-6 induced "signal transduction" by STAT3 from the plasma membrane to a cytoplasmic membrane destination for yet to be elucidated function(s) in the cytoplasm including prolongation of signaling and/or cross talk. STAT 3 and androgen receptor signaling are inactivated in androgen-dependent LNCaP cells after administration of Saw Palmetto The up-regulation of COX-2, p-Stat3, and p-Stat5 may be correlated to the carcinogenesis of ESCC. The activation of Stat3 is correlated to the aggressive behavior of ESCC. dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem hyper-immunoglobulin E syndrome (HIES) phosphorylated STAT3 and Akt play an important role in pathogenesis of malignant tumors of the epidermis Sodium arsenite dose dependently alters STAT3 and JAK2 activities via Bcl-6 and this may have a role in arsenic-associated carcinogenesis. Stat3 has an important role in the early stages of epithelial carcinogenesis as well as a novel role in malignant progression of skin tumors in a transgenic mouse model. STAT3, Runx2, and steroid receptor coactivator-1 are critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF (thoracic ossification of ligament flavum) STAT3 tyrosine phosphorylation occurs in preformed transducer complexes that can be activated in the absence of intact lipid rafts or caveolin. The combined data suggest that STAT3 tyrosine phosphorylation occurs in preformed transducer complexes that can be activated in the absence of intact lipid rafts or caveolin. in angiosarcoma, significant correlation was seen between phosphorylated-STAT3 and cyclin D1 but not between phosphorylated Akt and cyclin D1 The role of the STAT3 pathway in the regulation of IL8 transcription by Ox-PAPC in vitro and in atheroclerosis in vivo is reported. Inhibition of exportin-1-mediated nuclear export slowed down nucleocytoplasmic shuttling of v-Src-activated STAT3 resulting in reduced tyrosine phosphorylation, decreased induction of STAT3 target genes and increased apoptosis. ET Patients lacking the JAK2V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and suppressor of cytokine signaling-2. In addition, JAK2V617F-negative patients showed lower levels of STAT3 phosphorylation siRNA specifically and efficiently blocks the constitutively activated STAT3 signaling pathway in human esophageal squamous carcinoma cells. strong expression of cytoplasmic inactive STAT3 in NSCLC and malignant mesothelioma cases implies a major role for STAT3 in tumor motility, invasion, and metastasis via a nontranscriptional pathway Stat3alpha and Stat3beta have distinct intracellular dynamics, with Stat3beta exhibiting prolonged nuclear retention and reduced intranuclear mobility especially following ligand stimulation Ursolic acid is a novel blocker of STAT3 activation that may have a potential in prevention and treatment of multiple myeloma and other cancers. ATF2/STAT3 signaling pathways are activated and may play a role in development of eccrine porocarcinoma and eccrine poroma. PKCepsilon activation is essential for constitutive activation of Stat3 and prostate cancer progression. The IL-6/STAT3 antiapoptotic pathway is induced by short exposure to bile acid cocktail and low pH. IFNalpha is able to interfere with IL-6 signaling by inhibiting STAT3 activity and the abrogation of STAT3 activity accounts for the ability of IFNalpha to induce apoptosis in myeloma cells. Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains. Together, these data demonstrate that NDRG2 expression in breast cancer cells is able to inhibit STAT3 activation via SOCS1 induction in a p38 MAPK dependent manner. low p-STAT3 in GCs may account for decreased fertilization, implantation, and pregnancy rates of in vitro fertilization in polycystic ovarian syndrome women CTR9 participates in the transcription of IL-6-responsive genes through the regulation of DNA association of STAT3 and modification of histone methylation In breast cancer stem-like cells, the STAT3 pathway was found to be positively regulated by mTOR signaling, whereas PTEN served as a negative regulator of both STAT3 and mTOR signaling. EGFR induces expression of IRF-1 via STAT1 and STAT3 activation leading to growth arrest of human cancer cells Observations suggest that suppression of Stat3 signaling may provide a potential therapeutic approach to overcoming DOX resistance in metastatic breast cancer cells. The activation of AKT and NF-kappaB, but not STAT3, significantly contributes to the progression of breast cancer. Following cell exposure to IL-15, phosphorylation of STAT5 was predominantly observed, whereas, following stimulation with IL-21, there was predominant STAT1 and STAT3 activation. define a second oncogenic pathway, STAT3 activation, which operates in activated B-cell-like Diffuse large B-cell lymphoma an IL-6-inducible STAT3 and CDK9 binding to the proximal gamma-FBG promoter as well as increased loading of RNA Pol II Thus the c-myc P2E behaves as a dual-purpose STAT3 element with anomalous characteristics in HepG2 cells. the potential mechanism by which cell-cell contact initiates STAT3 activation. human breast cells are a uniquely permissive environment for HGF transactivation by Src/Stat3 which may allow for the inappropriate activation of HGF transcription during the early stages of breast transformation We conclude that Stat3 binding is important for MASP2 promoter activity. Blocking Hsp90 disrupts IGF-I and IL-6-induced proangiogenic signaling cascades by targeting IGF-IR and STAT3 in pancreatic cancer Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case. anti-apoptotic effects of STAT3 signaling in gastric cancer cells by enhancing Akt activation, Bad phosphorylation and Bcl-xL is mediated by REG Ialpha expression Reduced endometrial pSTAT3 and IL-11 may be involved in secretory transformation of glandular epithelium during receptivity. Reduced IL-11 production and STAT3 phosphorylation may contribute to unexplained infertility in some women. A model for binding of phosphopeptides to SH2 domain of STAT3 was presented. YC-1 inhibited Stat3 activity by enhancing the polyubiquitination of P-Stat3(705) induced by cisplatin. EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment. The expression of STAT3 and p38 was positively correlated with the degree of dysplasia in sporadic colorectal tubular adenoma. the astroglial differentiation effect of AICAR on neural stem cells was acting independently of AMPK and that the JAK-STAT3 pathway is essential for the gliogenic effect of AICAR. SN acts directly on neurons after hypoxia and ischemic insult to further their survival by activating the Jak2/Stat3 pathway. Regulates ATP-binding cassette transporter 3 (ABCA3) expression in vivo and in vitro. STAT3 mediates resistance to ATP depletion-induced apoptosis of proximal tubular epithelial cells, which may be a potential target in treatment of renal ischemic injury. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma variations in cell density can profoundly modify the extent of JAK-mediated persistent STAT3 phosphorylation; however, STAT3 activation was not sufficient to provide critical growth and survival signals in melanoma cell lines The Ang II/Rac1/STAT3 pathway is an important signaling pathway in the atrial myocardium to mediate atrial structural remodeling, and losartan and statin may be able to reverse Ang II-induced atrial structural remodeling in atrial fibrillation. a network involving signal coactivation of NF-kappaB and STAT3, differentially modified by p53 inactivation or mutation, promotes altered BAX/BCL-XL expression and cell survival in HNSCC. potential coordinative effects of Wnt, NF-kappaB and/or Stat3 activation on gastric cancer formation presumably by promoting the transcription of their common target genes. Abnormal STAT3 signalling in T cells from Sjogren's syndrome patients. Sp1 recruits ATF3, c-Jun, and STAT3 to obtain the requisite synergistic effect in neuronal injury through DINE neuronal injury-inducible gene Interferon gamma induces XAF1 and Noxa expression and potentiates apoptosis by STAT3 activation autoregulation of DeltaNp63 gene transcription is mediated through activation of STAT3 and its subsequent binding to the STAT3RE. Results suggest that STAT3 siRNA can inhibit the invasion ability of colon cancer cells through inducing anoikis, which antiapoptotic genes survivin and Bcl-xL contribute to regulation of anoikis. LMP1 stimulated STAT3 Tyr 705-dependent nuclear accumulation, as well as the phosphorylation of STAT3 at both Tyr 705 and Ser 727. identify leptin/STAT3 signaling as a novel pathway for survivin expression in breast cancer cells an essential role of the SH2B1 variants in the activation of the Src kinase and the resulting mitogenic response--extending to phenotypic cell transformation and involving the established Src substrate STAT3. HOXA1 partially mediates oncogenic transformation of the immortalized human mammary epithelial cell through modulation of the STAT3 and STAT5B pathways. pSTAT3 is a potential biomarker of melanocytic transformation and progression Nuclear accumulation of STAT3 activation by IL-6 plays a key role in iNOS expression and resultant DNA damage, leading to EBV-mediated Naso-Pharyngeal Carcinoma(NPC). Novel mitogenic signaling pathway in airway smooth muscle cells leading from PDGF to Stat3 and cell cycle gene regulation. Theses findings illustrate the biologic significance of JAK1, 2/STAT3 signaling in colorectal cancer (CRC) progression and provide novel evidence that the JAK/STAT3 pathway may be a new potential target for therapy of CRC. Stat1/3 directly controls promoter P1 of the CASR, and the Stats indirectly regulate promoter P2 of the CASR via Sp1/3 in response to IL-6 STAT3, Twist, and AKT2 form a functional signaling axis to regulate pivotal oncogenic properties of cancer cells STAT3 activation functionally mimicked IL-21 treatment and that STAT3-mediated BLIMP1 up-regulation occurred despite high BCL6 expression levels STAT3 activation is independent of the EGFR/MEK/ERK signaling pathway JAK-STAT3 signaling pathway participates in regulating the invasion and metastasis of human breast cancer. STAT3 activation mediates COX-2 expression and ischemic tolerance. Src-dependent STAT-3-mediated VEGF expression is a major mechanism of 14,15-EET-induced angiogenesis HER2-dependent transcriptional upregulation and protein secretion of MMP-7 are mediated by activated STAT3. The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) inhibits activation of the JAK1-->STAT3 pathway by forming adducts with both JAK1 and STAT3. STAT3 enhances invasiveness of tumours and trophoblast cells. PIM1 kinase plays a critical role in the STAT3 --> PIM1 --> NFkappaB stress response pathway Single nucleotide polymorphism in STAT3 gene is associated with ulcerative colitis HA binding to tumor cells promotes Nanog protein association with CD44 followed by Nanog activation and the expression of pluripotent stem cell regulators, and forms a complex with Stat-3 in the nucleus leading to Stat-3 and MDR1 activation Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells. lower levels of pSTAT3 were found in the nuclei of hepatitis E virus ORF3-expressing Huh7 human hepatoma cells stimulated with EGF. This results in downregulation of the acute-phase response, a major determinant of inflammation in the host. Results do not support a major role for STAT3 variants in BMI, obesity and insulin resistance in an adult male population. The Stat3-activating Tyk2 V678F mutant does not up-regulate signaling through the type I interferon receptor but confers ligand hypersensitivity to a homodimeric receptor Mutations are implicated in hyper-IgE syndrome. Epigallocatechin-3-gallate suppresses the pathological characteristics of keloids through inhibition of the STAT3-signaling pathway. These results indicate that the IL-6 family of cytokines modulates STAT3 activation by desumoylation and inactivation PML through SENP1 induction. Stat3 is involved in metastatic behavior of human prostate cancer cells and may provide a therapeutic target to prevent metastatic spread of primary prostate cancer. persistent activation of STAT1, STAT3, and STAT5 correlate with resistance to vorinostat in lymphoma cell lines nuclear STAT3 expression is associated with poor patient prognosis in the intestinal subtype a critical role for a EGF-R-connected p60c-src-kinase-mediated pathway involving STAT3 and contributing to cell survival and proliferation within colorectal carcinomatumours. Y14 interacts with STAT3 and regulates the transcriptional activation of STAT3 by influencing the tyrosine-phosphorylation of STAT3. KLF11 may interfere with glucose homeostasis in a Danish general population and that STAT3-mediated up-regulation of KLF11 transcription was impaired by the -1659G>C variant. Down-regulating signal transducer and activator of transcription 3 (STAT3) expression by short hairpin RNA in Smad4-deficient cells prevented TGFbeta-induced invasion Platelet-derived growth factor-induced cell growth, migration, and IL8 secretion in corneal fibroblast involve the JAK2-STAT3 signaling pathway. This study uncovers a novel link between STAT3 and interleukin 8, the deregulation of which plays a key role in the malignant behavior of glioblastoma cells. In addition, STAT3 knockdown inhibited anchorage-independent growth and induced apoptosis in CAOV3 cells, and decreased tumor growth in nude mice implanted with ovarian cancer cells. Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous squamous cell carcinoma, Bowen's disease and basal cell carcinoma. parvovirus B19 NS1 protein modulates inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells There is a marked increase in STAT3 activation in many forms of glomerulonephritis. The correlation of STAT3 activation with clinical and histologic parameters suggests that this pathway plays an important role in the pathogenesis of kidney disease. IL-6 treatment induced MUC4 expression through the gp130/STAT3 pathway, indicating the direct role of IL-6 on the activation of the intestinal mucin gene MUC4 in gastric cancer cells nonoverlapping, sequential activation of STAT3 and STAT5 selects for multilog expansion, programming, and dendritic cell DC1 polarization of tumor-competent DCs from CD34(pos) cells Data show that platelet-derived growth factor-BB induces mesenchymal stem cell proliferation via activation of the Jak2-Stat3 transcription cascade. Genome-wide association study of gene-disease association. (HuGE Navigator) a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17-secreting cells due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo. The importance of STAT3 signaling in maintenance and survival of medulloblastoma cells. heterozygous STAT3 mutations were identified in 34 of 35 unrelated Hyper-IgE syndrome families; patients had impaired T(H)17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation results suggest that STAT3 is a target of beta-catenin/TCF pathway and might participate in esophageal tumorigenesis Stat3 is a potent oncogenic molecule that plays a role in formation of lung adenocarcinomas in both mice and humans. The PSMA promoter/enhancer-driven shRNA also depressed the expression of STAT3 in only prostate cancer cells These findings show a novel mode by which HIF-1alpha is regulated not only in cancer cells but also in the tumor-associated inflammatory cells, suggesting Stat3 as an important molecular target for inhibiting the oncogenic potential of HIF-1. Cucurbitacin B inhibited cell proliferation and induced apoptosis of Hep-2 cells by suppressing the STAT3 signal pathway, and down regulating the expression of cyclin B1 and Bcl-2 proteins. Data show that Stat3 activation and its interaction with Ec-gp96, which in turn interacts with E. coli outer membrane protein A, are critical for E. coli invasion. the loss of PIAS3 in glioblastoma multiforme contributes to enhanced STAT-3 transcriptional activity and subsequent cell proliferation the Th2 cytokine IL-21 is abnormally expressed in Hodgkin lymphoma cells, which regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha Significant p-STAT3 expression is associated with colorectal adenocarcinoma. overexpression of p-ATF2, p-STAT3 and possibly p53, but not p63 or p73, may contribute to the tumorigenesis of cutaneous vascular tumors. Wnt (Wnt2), Stat3, and Notch-1 and -2 signaling are correlated in human epidermal tumors. Novel H332Y mutation may result in the loss of function of STAT3 and leads to the hyper-IgE syndrome phenotype. Enhanced STAT3 signaling responsiveness to proinflammatory factors may impact on mechanisms of muscle repair and regeneration. Plays a role in the pathogenesis of gestational trophoblastic disease, probably through the regulation of apoptosis. Co-stimulation of G(s) and G(q) can result in the fine-tuning of STAT3 activation status, and this may provide the basis for cell type-specific responses following activation of hIP. Two cases of hyperactivated STAT3 in ALK-positive diffuse large B-cell lymphoma with clathrin-ALK fusion are reported. High expression and activation of STAT3 exist in laryngeal carcinomas. STAT3 expression was significantly related to overall 5-year survival rate in breast cancer patients. This review summarizes the current understanding of the roles of STAT3 in IBD and the potential of targeting STAT3 for the treatment of IBD, emphasizing recent observations [review] STAT3 activation and nuclear accumulation in response to Hepatocyte Growth Factor requires nuclear-proximal activated c-Met. STAT3 NH(2)-terminal domain plays an important role in the interleukin-6 signaling pathway by interacting with the p300 bromodomain, thereby stabilizing enhanceosome assembly. JAK/STAT3 and ERK1/2 signaling activation is involved in leptin-mediated proliferation of renal cell carcinoma Caki-2 cells Our study suggests a potential role of the STAT3 polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity. green tea extract inhibits angiogenesis partly through the disruption of STAT3-mediated transcription of genes STAT3 constitutive activation, alone and in concurrence with EGFR expression, plays an important role in high-grade/malignant gliomas and targeting STAT3/JAK2 sensitizes these tumors to anti-EGFR and alkylating agents S727 phosphorylation is sufficient to activate Stat3, thereby driving prostate tumorigenesis independent of Y705 phosphorylation. STAT3 single-nucleotide polymorphisms and STAT3 mutations associated with hyper-IgE syndrome are not responsible for increased serum IgE serum levels in asthma families Expression of EBV LMP1 is positively correlated with Fascin, pStat3 and the proliferation index of tumor cells in nasopharyngeal carcinoma. BDNF- and seizure-dependent phosphorylation of STAT3 cause the adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. elevated Stat3 phosphorylation in 19 of 100 (19%) bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. combined use of IFN-alpha and IL-21 boosts STAT3 signaling, cytotoxicity, and anti-tumor efficacy, suggesting that a combinatorial therapeutic use of these cytokines may benefit cancer patients. TCPTP is a negative regulator of SFK, JAK1 and STAT3 signalling during the cell cycle. Stat3 played an important role in the G1 to S phase transition in laryngocarcinoma cells. mutations cause autosomal-dominant hyper IgE syndrome; lead to disruption of cytokine signaling pathways Results suggest that STAT3 decreases the pVHL-mediated ubiquitination of HIF-1alpha through competition with pVHL for binding to HIF-1 alpha, and then stabilizes HIF-1alpha protein levels. IL11 inhibits human extravillous trophoblast invasion via STAT3, indicating a likely role for IL11 in the decidual restraint of EVT invasion during normal pregnancy. These results support the hypothesis that STAT3 and CREB play an important role in leptin signaling pathway that leads to the proliferation of Ishikawa cells, thus establishing a direct association between obesity and endometrial tumorogenesis. S-glutathionylation of STAT3, a modification that may exert regulatory function in STAT3 signaling. data indicate overexpression of mesothelin in pancreatic cancer cells leads to constitutive activation of Stat3, resulting in enhanced expression of cyclin E & cyclin E/cyclin-dependent kinase 2 complex formation & increased G(1)-S transition STAT3 was expressed at higher levels in patients with diabetic nephropathy than in control subjects. guggulsterone not only induces apoptosis, but also inhibits angiogenesis and metastasis in colon cancer cells by blocking STAT3 and VEGF expression EBNA2 is a transcriptional coactivator of STAT3 by influencing its DNA-binding activity. FoxO1 binds to STAT3 and prevents STAT3 from interacting with the SP1.POMC promoter complex, and consequently, inhibits STAT3-mediated leptin action. Cell confluency-induced Stat3 activation regulates NHE3 expression by recruiting Sp1 and Sp3 to the proximal NHE3 promoter region during epithelial dome formation. LKB1 protein might inhibit malignant biological behavior of A549 cells partly by down-regulating the tyrosine-phosphorylated level of STAT3 protein. There are associations with JAK2 and STAT3 implicating the role of this signaling pathway in inflammatory bowel disease. Activated STAT3 is a required part of the continuous activation of B3/B4 genes, which protects tumor cells from dying. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator) mutations in the STAT3 gene in most of the patients with type 1 hyper-IgE syndrom (Review) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1).( Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. In this review, studies of STAT3 deficiency in humans highlight nonredundant roles of STAT3 in diverse cellular processes such as antimicrobial immunity and protection at epithelial barriers, and in hyper-IgE syndrome. STAT3 analysis of essential thrombocythemia shows that in about half of patients, STAT3 hyperactivation is independent of JAK2 mutations. The hyperactivation of STAT3 by JAK2 mutations or promoter activation may be a critical step in development of ET. These results indicate that HDAC3 may act as a scaffold protein for PP2A to regulate the LIF/STAT3-mediated signaling pathway. STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors Interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is modulated by interleukin-6. Results indicate that H. pylori CagA activates the STAT3 signaling pathway in vitro and in vivo, providing a potential mechanism by which chronic H. pylori infection promotes the development of gastric cancer. there was a statistically significant dependence of the EGFR status on STAT3 expression in neoplastic tissues Site-directed mutagenesis of all four putative STAT3-binding sites in the SALL4 promoter significantly reduced its responsiveness to STAT3, although the most dramatic effect was seen at the binding site starting at -199. G-Gly inhibits apoptosis in Barrett's oesophagus and oesophageal adenocarcinoma via mechanisms distinct from those activated by G-17 and involving JAK2 and STAT3 activation. Antisense oligodeoxynucleotides that inhibited Stat3 could induce apoptosis and suppress cell proliferation in laryngeal carcinoma Hep-2 cells. STAT3 expression in gastric cancer indicates a poor prognosis. BITC (benzyl isothiocyanata) induces apoptosis in some types of pancreatic cancer cells by inhibiting the STAT-3 signaling pathway. STAT3 transactivates its target genes by the recruitment of CBP/p300 co-activators and this process generally does not require the contribution of SRC-1. Sustained Src inhibition results in signal transducer and activator of transcription 3 (STAT3) activation and cancer cell survival via altered Janus-activated kinase-STAT3 binding. IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Observational study and genome-wide association study of gene-disease association. (HuGE Navigator) STAT3 physically interacts with stathmin to regulate microtubule dynamics in migrating T-cells. These results indicate that MAGOH regulates the transcriptional activation of STAT3 by interfering complex formation between STAT3 and Y14. Data show that the mechanism of G-CSF-induced chemotaxis appears to involve the phosphorylation of JAK1/STAT3 pathway. Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator) IL-12 stimulates the OIP-1 gene expression through STAT-3 activation in CD4+ T cells STAT3 mediates negative regulation of hepatic gluconeogenic gene expression in vivo by interacting with regulatory regions of these genes. STAT3 activation is critical in IL-17A-mediated CC chemokine ligand 11 (CCL11) expression in human airway smooth muscle cells. Data indicate an almost universal expression of activated Stat3 in benign and malignant salivary gland tumors. experiments demonstrate that Stat3 has both - tumor suppressing and tumor promoting properties -ATF2 and p-STAT3 are concordantly overexpressed in extramammary Paget's disease and their expressions may possibly be associated with the tumor stage. Data suggest that STAT3 activation contributes to the survival and proliferation of OSA cells, thereby providing a potentially promising target for therapeutic intervention. This study indicates that phosphatidic acid acts as an important mediator for increasing Bcl-2 expression through STAT3 (Ser727) activation via the ERK1/2 MAPK pathway. Role of RAF/MEK/ERK pathway, p-STAT-3 and Mcl-1 in sorafenib activity in human pancreatic cancer cell lines. Diesel particle-induced transcriptional expression of p21 involves activation of EGFR, Src, and Stat3 mTOR signaling is one major mechanism in a tightly regulated network of intracellular signal pathways including the JAK/STAT system to regulate invasion in human trophoblast cells by secretion of enzymes that remodel the extra-cellular matrix. Data suggest that colorectal neoplasms are STAT3/pSTAT3 immunoreactive in a stage specific manner and STAT3 protects cancerous colorectal epithelial cells from apoptosis. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. A novel mutation in the linker domain of the signal transducer and activator of transcription 3 gene, p.Lys531Glu, in hyper-IgE syndrome. Targeting Stat3 signaling using siRNA may serve as a novel therapeutic strategy for the treatment of breast cancers expressing constitutively activated Stat3. Focusing on how STAT3 work in concert with other transcription factors will hopefully provide a better mechanistic understanding of the pathogenesis of various autoimmune diseases. persistent activation and nuclear translocation but not upregulation of STAT3 occurs in ALS spinal cord microglia. The JAK3/ERK pathway may play an important role in epidermal growth factor induced MMP-9 expression in SKBR3 cells. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. STAP-2 is phosphorylated at Tyr250 by Brk, and plays an important role in Brk-mediated STAT3 activation. There was a significant correlation between the expression of p-STAT3 and that of osteopontin in melanoma. EGFR, NFkappaB, and STAT3 are required for human iNOS gene induction in proximal tubule cells in response to pressure or EGF, indicating a similar mechanism of activation. activated STAT3 is highly present in glioma but not normal brain tissues STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target. interactive effect between HPV 16/18 and transcriptional activation of STAT3 gene in cervical carcinogenesis STAT3 is frequently found to be constitutively active in breast cancer and tumors can become addicted to STAT3. Review. These findings suggest that kahweol inhibited A549 cell growth and induced apoptosis via down-regulation of STAT3 signaling pathway. Data show that ARHI could compete for Ran-importin binding and induce disruption of importin-binding to cargo proteins, including STAT3. GATA-1 can reverse STAT3-mediated gamma-globin gene silencing in erythroid cells Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways. Data show that blockade of endothelial cell-derived IL-6, CXCL8, or EGF by gene silencing or neutralizing antibodies inhibited phosphorylation of STAT3, Akt, and ERK in tumor cells, respectively. Using a model system of paired breast cancer cell lines, we found that coactivation of STAT5 and STAT3 leads to decreased proliferation and increased sensitivity to the paclitaxel and vinorelbine compared with cells that have only STAT3 activation. The EGF/PI3K/STAT3 signaling is identified as an essential pathway regulating VEGF and leptin expression in EGF-responsive colon cancer cells. Data show thatCypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. Data show that in the nucleus, the acetylated STAT3 dimer is associated with CD44 and binds to the cyclin D1 promoter, leading to increased cyclin D1 expression and cell proliferation. Stat3 is an essential signaling component potentially contributing to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia caused by PTPN11 gain-of-function mutations malignant transformation by activated Ras is impaired without STAT3; STAT3 was detected in mitochondria; findings show STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation findings suggest that Stat3 and p53 are cooperatively involved in the development of renal cell carcinoma (RCC) but assessment of their mRNA expression may not be useful for predicting the prognosis of patients with RCC mechanisms underlying different forms of hyper IgE syndrome and their functional outcome by investigating the incidence of STAT3 mutations and the competency of TH17 cell differentiation in a cohort of affected Turkish children were elucidated. constitutively activated STAT3 regulates expression of MUC1, which mediates lung cancer cell survival and metastasis in vitro and in vivo. These results suggest that IkappaB-zeta is a negative regulator of STAT3, and demonstrate a novel mechanism in which a component of the NF-kappaB signaling pathway inhibits the activation of STAT3. Studies indicate that STAT3 plays dual tumor suppressive and oncogenic roles in glial malignancy depending on the mutational profile of the tumor. Findings suggest that STAT3 might be an excellent target for therapeutic intervention in tumor metastases. Lipopolysaccharide-squamous cell carcinoma-monocyte interactions induce cancer-supporting factors leading to rapid STAT3 activation. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. these findings support the enhancement of JAK3/STAT3 activation and cell growth in anaplastic lymphoma kinase positive - anaplastic large cell lymphoma via IL-21 signaling. A431 cells (human squamous cell carcinoma cells with EGFr overexpression) were found to be sensitized to radiation after treatment with STAT-3 small interfering RNA (siRNA). study concludes that Stat3 controls a specific gene set in trophoblast-like JEG-3 cells hypoxia-induced STAT3 activation is responsible for chemoresistance. IL-6, but not IFN-gamma, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes Data show that deletion of the C-terminal part of IL-22R dramatically decreased its ability to activate STAT3. p-Stat3 expression in cervical cancer acts as a predictor of poor prognosis. Data show that restoration of GRIM-19 levels reestablishes the control over STAT3-dependent gene expression and tumor growth in vivo. STAT3 has a critical role in regulating ovarian cancer cell motility and this process can be prevented by curcumin. Cholestasis or its important component-hydrophobic bile acids-can downregulate hepcidin expression through inhibiting IL-6-induced STAT3 phosphorylation and pSTAT3 protein nuclear translocation. TYK2 and STAT3 are genetic determinants of Crohn's disease in the Japanese population. These data suggest that STAT3 regulates the growth and self-renewal of GBM-SCs and is thus a potential target for cancer stem cell-directed therapy of glioblastoma multiforme. pSTAT3tyr705 may be a novel prognostic marker for poorer clinical outcome following curative resection and adjuvant therapy in gastric cancer Observational study and genome-wide association study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) Studies indicate that a better understanding of the mechanisms of dysregulation of the STAT pathway and leukemogenesis may serve as a basis for designing novel therapeutic strategies directed against STATs. This study not only reveals a role of CRT in motility promotion and anoikis resistance in ESCC cells, but also identifies CRT as an upstream regulator in the CRT-STAT3-CTTN-Akt pathway. chronic inflammatory demyelinating polyradiculoneuropathy(CDIP)patients with active disease showed higher pSTAT1, T-bet, & pSTAT3 in CD4(+) T-cells & monocytes than controls Studies have demonstrated that mutations in STAT3 and TYK2 genes result in Hyper-IgE syndrome (HIES. data suggests that, in at least certain cellular microenvironments, cell:cell interactions represent a novel way to activate STAT3 signaling, uncouple APC activation events and consequently regulate immunity and tolerance aStudies indicate that the phosphorylation of STAT-3 at serine 727 may regulate its activity negatively or positively. Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas. we have identified a novel regulatory pathway involving increased gene expression of the SNAT2 isoform mediated by a STAT-dependent pathway, which links IL-6 to increased activity of amino acid transporter system A cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway Visfatin through STAT3 activation enhances IL-6 expression that promotes endothelial angiogenesis. The upregulation of IL-8 production is caused by constitutive STAT3 activation at the level of gene transcription in melanoma cells. Tensile stress can activate the expression of p-ERK and p-STAT3 in alveolar epithelium A549 cells. STAT3 played an important role in the response and signal transduction of bronchial epithelial cells to the cyclic mechanical stretch stimulation through the phosphorylation of STAT3 Tyr705. STAT3 gene polymorphisms influences the risk of abdominal obesity, which is modulated by dietary saturated fat inttake. deguelin presents a potent anti-proliferative effect in part via the down-regulation of survivin expression and STAT3 phosphorylation in HTLV-1-transformed cells. Molecular dynamics simulations were performed in explicit water of the activated Stat3 homodimer, and also its closely related member of the STAT family, activated Stat1 homodimer. Observational study of gene-disease association, gene-gene interaction, and gene-environment interaction. (HuGE Navigator) ATRA blocks Squamous cell carcinoma (SCC) of the skin tumor formation, at least in part, by targeting events upstream of Stat3 The Stat3/5-dependent activation of cytokine expression in osteoblasts may have a significant impact on cancer cell migration and proliferation, but also on osteoclast activation. STAT3 is a weak anti-apoptotic agent Studies suggest that a STAT3-SCLIP interaction is required to preserve SCLIP stability and contributes to the maintenance of normal epithelial morphology. Taken together, these data show that mt p53 (G199V) gains antiapoptotic function mediated by STAT3 in ATC cells. tumor-associated STAT3 is silenced by an oncolytic adenovirus STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways. analysis of reciprocal regulation of c-Src and STAT3 in non-small cell lung cancer STAT3 as a novel mediator of nutrient signals and identifies a Ser(727) phosphorylation-dependent and Tyr(705) phosphorylation-independent STAT3 activation mechanism in the modulation of insulin signaling. detected ERalpha binding to STAT3 and JAK2 (Janus kinase 2), resulting in enhanced JAK2 activity upstream of STAT3 in response to leptin that might lead to an increased ERalpha-dependent cell viability baicalein not only inhibited IL-6-mediated phosphorylation of signaling proteins, such as Jak, STAT3, MAPK, and Akt, but also inhibited the expression of their target genes, such as bcl-xl. Elevated levels of STAT3 protein are characteristic of Burkitt lymphoma cells refractory sto EBV lytic cycle induction by HDAC inhibitors. Data suggest that the percentage of peripheral blood mononuclear cells displaying p-STAT-3 may be increased in malignant glioma patients. A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. Studies indicate that signaling pathways of STAT3, NOTCH, hedgehog and transforming growth factor-beta (TGFbeta), which are involved in stem cell renewal, differentiation, survival, and are commonly deregulated in HCC. data suggest an important role for the negative regulatory effect of PIAS3 on STAT3 in EGF-driven tumors the human SREBP-1c promoter was positively regulated by insulin and negatively regulated by STAT3. This study demonstrates in a cellular model and in patients with tuberculosis that in addition to p38 and NF-kappaB, STAT3 has a key role in driving fibroblast-dependent unopposed MMP-1 production that may be key in tissue destruction in patients. The downregulation of miR-21 contributes to the antitumor effects of IFN-beta and that miR-21 expression is negatively regulated by STAT3 activation. findings suggest that overexpression of p-STAT3 (Tyr705) occurs in urothelial carcinoma, and that pathways other than SOCS3 may contribute to its activation in this cancer STAT3 activation is associated with Mcl-1 expression in nasal NK-cell lymphoma ERp57 is a necessary cofactor for the regulation of at least a subset of STAT3-dependent genes. the activation of JAK/STAT3 pathway by GHRH The STAT3 signal pathway regulates cell proliferation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma cells. study indicates that IL-6 induces a novel STAT3-APE1 complex, whose interaction is required for stable chromatin association in the IL-6-induced hepatic acute phase response these findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB. In human glioma, expression of C/EBPbeta and STAT3 correlates with mesenchymal differentiation and predicts poor clinical outcome Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. Specific siRNA targeting STAT3 gene is able to enhance the radiosensitivity in Hep-2 cells by regulating expression of Bcl-2, VEGF and p53 proteins. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients. The STAT3 has an important role in the occurrence and development of human meningioma by regulating VEGF expression. Expression of a constitutively activated STAT3 mutant or myristoylated AKT partially blocked the effects of sunitinib in these tumor cells. These findings indicate that cancer-initiating cells contribute to the immune evasion of glioblastoma multiforme and that blockade of the STAT3 pathway has therapeutic potential. Levels of STAT3 mRNA correlate with polymorphic differences in genes encoding interferon alpha signal transduction components and might account for different patient responses in chronic myeloid leukemia. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) Plumbagin inhibits STAT3 activation pathway through the induction of SHP-1 and this may mediate the sensitization of STAT3 overexpressing cancers to chemotherapeutic agents. These results indicate that Stat3 plays a key role in the invasion and apoptosis of human glioma cell line U251. Data suggest that INCB16562 is a potent JAK1/2 inhibitor and that mitigation of JAK/STAT signaling by targeting JAK1 and JAK2 will be beneficial in the treatment of myeloma patients, particularly in combination with other agents. Data show that LLL12 inhibited STAT3 phosphorylation, induced apoptosis as indicated by the increases of cleaved caspase-3 and poly (ADP-ribose) polymerase, and also downregulated cyclin D1, Bcl-2, and survivin at both protein and messenger RNA levels. Stat3 could be the major target for increasing chemosensitivity in patients who develop chemoresistance during chemotherapy. Human placental multipotent mesenchymal stromal cell-conditioned medium activated STAT3 expression in endothelial cells, supporting cell survival. STAT3 activation and SOD2 production protect against oxidative stress-induced endothelial cell damage. Carrying either the JAK2 or STAT3 IBD risk allele was associated with significantly enhanced susceptibility to DNA damage, as estimated by comet assays lack of spontaneous STAT3 and STAT5 activation and the normal response to TPO is unexpected as MPLW515L leads to constitutive receptor activation and hypersensitivity to TPO in experimental models The mRNA expression levels of EGFR and STAT3 in laryngeal papilloma tissue were significantly higher than that in normal laryngeal tissue. p-STAT3 expression was correlated with recurrence and metastasis. A chemical genetics approach reveals STAT3 as a novel neurofibromin/mTOR pathway signaling molecule, define its action and regulation, and establish STAT3 as a tractable target for future NF1-associated cancer therapy studies. Data suggest that the up-regulation of CR-1 and p-STAT3 may play important roles in gastric carcinogenesis and lymph node metastasis demonstrates that antiphospholipid antibodies limit trophoblast cell migration by downregulating trophoblast IL-6 secretion and STAT3 activity. These findings indicate the existence of the nuclear EGFR/EGFRvIII signaling pathway in GBM and its functional interaction with STAT3 to activate COX-2 gene expression. constitutive activation of Stat3 signaling pathway may play an important role in the invasion and prognosis of epithelial ovarian carcinoma. data suggest that the novel G342D mutation affects the binding of STAT3 on DNA and the STAT3-dependent expression of retinoid-related orphan receptor gammat mRNA, leading to the hyper-IgE syndrome phenotype. constitutive phosphorylation of STAT3 on serine 727 residues is a hallmark of CLL and that STAT3 be considered a therapeutic target in this disease. STAT3 represents a shared risk locus for multiple sclerosis and Crohn disease. p-STAT3 levels are decreased in chronic rhinosinusitis with nasal polyps despite increased levels of IL-6 and sIL-6R and are associated with the absence of an IL-17 response In 64 patients with hyper-IgE syndrome, we identified 31 different STAT3 mutations, 18 of which were novel. ZIP4 overexpression causes increased IL-6 transcription through CREB, which in turn activates STAT3 and leads to increased cyclin D1 expression Expressions of STAT3 show mutual correlations in primary ductal breast cancers, which suggest co-operation among the protein. Stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas Stat5b has a preferential role in the promotion of prostate cancer cell viability and tumor growth 5-aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling Targeting STAT3 may enhance treatment efficacy against pancreatic cancer. Treatment of a glioblastoma stem cell line culture with a STAT3 phosphorylation inhibitor (WP1193) or 10% FBS (fetal bovine serum) both led to a decrease in expression of the stem cell marker CD133, but differed in phenotype changes. Data show that the STAT3 haplotype conformed by the risk alleles of each polymorphism was significantly associated with both clinical phenotypes of IBD. STAT3 inhibition using si-RNA suppressed VEGF secretion in the SNU-1041 head and neck cancer cell line STAT3 has a role in in vitro transformation triggered by TRK oncogenes STAT3 inhibition downregulated the expression of Bcl2 family of anti-apoptotic gene Bcl-xL. IL-6/STAT3/TFF3 signaling is involved in human biliary epithelial cell migration and wound healing. VEGF expression in breast cancer cells is mediated by HIF-1 and STAT3 in a miR-20b-dependent manner. IR induces Bcl-X(L) accumulation via STAT3, which then promotes cancer cell invasion and epithelial-mesenchymal transition(EMT)-associated markers. the phosphorylation status of CagA affects the signal switch between the SHP2/ERK and JAK/STAT3 pathways through gp130, providing a novel mechanism to explain H. pylori signaling. Treatment of lymphocytic choriomeningitis virus Armstrong-infected Stat3 conditional knockout mice induces neither immune suppression or T cell deletion. the immunosuppressive effects of IL-10-STAT3 on MHC-II antigen presentation may occur via the inhibition of cathepsin S expres Stat3 and Cyclin D1 were overexpressed in laryngeal neoplasm tissue, and they have a positive relationship. Over-expression of JAK/STAT signal pathway may be an important feature of hepatocellular carcinoma. High nuclear STAT3 expression levels are not associated with head and neck squamous cell cancers. Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator) amplified FGFR expression engages the STAT3 pathway Stat3 activation is induced by hydrogen peroxide exposure to the skin in healthy individuals JAK2/STAT3/vimentin signaling pathway participates in regulating the proliferation and migration of human colon cancer cells. Src kinase-mediated activation of STAT3 and subsequent angiogenic gene expression mediate the effects of integrin alpha v beta 5 and may be exploited to enhance the paracrine activities of circulating angiogenic cells. we studied the immunohistochemical expression of STAT-3 proteins in primary central nervous system lymphomas HBx-mediated down-regulation of let-7a and up-regulation of STAT3 supports cell proliferation in HBx cells. Stat3 activation in UV-exposed skin is one of the initial events where DNA damage and ROS are involved. Stat3 pathway is overexpressed in multidrug resistant osteosarcoma cells. CDDO-Me significantly inhibited Stat3 phosphorylation, Stat3 nuclear translocation and induced apoptosis in osteosarcoma. These data identify atypical PKC isozymes as STAT and ERK activators that mediate c-fos and collagenase expression. IL-22, likely via activation of STAT3 and downstream genes (e.g., SOCS3), is able to protect against cell stretch and pulmonary baro-/biotrauma by enhancing epithelial cell resistibility High STAT3 is associated with the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas. Thymic stromal lymphopoietin induced proinflammatory gene expression in human airway smooth muscle cells involved ERK1/2, p38, and JNK, and STAT3 activation. Interferon-gamma-induced suppressor of cytokine signaling (SOCS)3 expression leads to inhibition of interleukin (IL)-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. genetic polymorphism is associate with Hyper-IgE syndrom (case report from Cina) significantly decreased cell viability and increased apoptosis in human neuroblastoma cell line in association with down-regulation of p-ERK1/2, p-Akt, p-STAT3 survival pathways. arecoline induces anoikis of HA22T/VGH cells involving inhibition of STAT3 and increased RhoA/Rock activation STAT3 is an important target for human GSCs in regulation of glioblastoma stem cells(GSCs) growth, apoptosis, differentiation and tumorigenic potential. The proportion of phosphorylated STAT3alpha relative to STAT3alpha was significantly greater in supratentorial PNETs than in medulloblastomas. the cdk5-STAT3 oncogenic pathway plays an important role in the expression of DNA repair genes and that these proteins could be used as predictive markers of tumors that will fail to respond to chemotherapy. These findings indicate that TRIM8 enhances the STAT3-dependent signal pathway by inhibiting the function of PIAS3. Interleukin-27 induces a STAT1/3- and NF-kappaB-dependent proinflammatory cytokine profile in human monocytes STAT3 plays crucial roles in osteosarcoma development simultaneous expression of HGF/c-met and three trasducers of tyrosine kinase receptors STAT3, PI3K, RHO in both nodular and extranodular tissues were studied by immunohistochemistry in 50 benign thyroid nodules, 25 associated with Hashimoto's thyroiditis LLL12, a STAT3 small molecule inhibitor, blocked IL-6-induced STAT3 phosphorylation, resulting in attenuation of the anti-apoptotic activity of IL-6. HIV-1 activation of STAT1 and STAT3 in human brain microvascular endothelial cells (HBMEC) is associated with induction of promoter activity of the interferon-stimulated response element (ISRE)/interferon-gamma-activated sequence (GAS). Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction. There was no difference in the distribution of allele and genotype in either JAK2 or STAT3 between ankylosing spondylitis groups and controls. Meta-analysis of gene-disease association. (HuGE Navigator) AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3). STAT3 was activated in primary mantle cell lymphoma cells either constitutively through a cytokine autocrine loop or in response to B-cell receptor engagement, both processes leading to a survival signal inhibited by bortezomib. Data show that STAT3alpha may therefore be a common mediator of oncogenic signaling pathways stimulating progression of EC. Data suggest that constitutively activated Stat3 binds to the ROR1 promoter and activates ROR1 in CLL cells. Data demonstrate that eradication of signal transducers and activators of transcription (STAT3) signaling considerably enhances BMP-induced osteogenic differentiation of hMSCs Our study provides evidence that the up-regulation of STAT-3 in colonic mucosa may be associated with the progression of ulcerative colitis. STAT3 is not only a downstream target of IL-6 but, with miR-21, miR-181b-1, PTEN, and CYLD, is part of the positive feedback loop that underlies the epigenetic switch that links inflammation to cancer. Observational study of genetic testing. (HuGE Navigator) Expression of a redox-insensitive STAT3 in breast carcinoma cells accelerates proliferation while reducing resistance to oxidative stress. Data identified the oncogenic transcription factor STAT3 as a binding partner of nuclear survivin. our results support the concept that STAT3 upregulates the protein expression and transcriptional activity of beta-catenin in breast cancer Cell-cell contacts induce STAT3 activity in colon carcinoma cells through an autocrine stimulation loop. Stat3 activation by IL-6 and IL-10 plays an important role in cell-to-cell interaction between tumor cells and macrophages in the ascites of advanced epithelial ovarian cancer (AdEOC). NF-kappaB and STAT3 transcription factors are especially important signaling hubs for integrating signal pathways to orchestrate effective host defense without excessive inflammatory injury. STAT3 was positively correlated with the neovascularization of nasal polyps, and was also positively correlated with VEGF expression. The expression of STAT3 and c-myc may play an important role in the tumorigenesis, metastases and poor prognosis of laryngeal squamous cell carcinoma. Abundant tyrosine phosphorylation of STAT3 leads to primary resistance to EGFR inhibitors in lung cancer. STAT3 activation mediates, at least in part, IFN-gamma-induced neurotoxicity and ICAM-1 expression by human astrocytes. Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells. Activated STAT3 directly bound to IL6 promoter and increased IL6 mRNA and protein secretion. STAT3 and c-Jun could physically interact and bind to the AP-1 site, implicating that the interplay of both transcriptional factors on the AP-1 site is responsible for isoproterenol-stimulated MMP-7 expression in gastric cancer cells. Lower expression of SSTR2 and activation of STAT3 in olfactory neuroblastoma cells might contribute to the development of ONB. A role was determined for signal transducer and activator of transcription 3 and Janus kinase-2 transduction in alpha4beta2 nicotinic receptor-mediated anti-inflammatory effects. We validated STAT3 as a bona fide target of BCL3 in a cervical cancer cell line by additional interference RNA and in silico analyses of previously reported lymphoma patients. Data show that in the presence of HPV16, STAT3 is aberrantly-expressed and constitutively-activated in cervical cancer which increases as the lesion progresses thus indicating its potential role in progression of HPV16-mediated cervical carcinogenesis. Adiponectin inhibits CRP production in HepG(2) cells elicited by IL-6, by downregulating STAT3 phosphorylation. Autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. results demonstrate for the first time that genetic polymorphisms in STAT3, TNFRSF1A and 2p15 are associated with ankylosing spondylitis in Han Chinese, suggesting common pathogenic mechanisms for the disease in Chinese and Caucasian European populations. Data show that STAT3 can transform into pSTAT3 to promote the survival and inhibit the apoptosis of gastric cancer cells. MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in Sezary syndrome. Data show that STAT3 binds to the SOCS3 promoter, and S727 is then phosphorylated, followed by the coincident binding of SET9 and dimethylation of K140, and lastly by the binding of LSD1. STAT3-dependent IL-22 signaling and effects in keratinocytes are negatively regulated by SIRT1 all of the phosphorylated STAT3 positive cells were also positive for phosphorylated STAT1, both of which could be inhibited by a JAK2/STAT inhibitor, AG490 Findings suggest that Stat3 could potentially be regulated to suppress IL-6 autocrine production in cancer cells to inhibit the progression of cancer and reduce drug resistance. butein exerts its antiproliferative and proapoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo a negativie correlation between the expressions of STAT3 and WWOX, but no relationship was found between WWOX and c-myc Activation of the IL-6/STAT3 pathway in transformed Barrett's epithelial cells enables them to resist apoptosis, indicating a possible contribution of the intrinsic inflammatory pathway to carcinogenesis in Barrett's esophagus. Hyperresponsiveness of transgenic glycoprotein (gp)130 mice to lipopolysaccharide involves specific upregulation of IL-6 in a gp130/STAT3- and Toll-like receptor 4/MyD88-dependent manner. Chr1q32 and STAT3 are ankylosing spondylitis susceptibility loci. STAT3-mediated leptin receptor signaling pathways may be activated in human colorectal adenomas. Inactivation of STAT3 in pancreatic cancer cell lines induces apoptosis but also may promote the expression of anti-apoptotic genes. NZB treatment determines an accumulation of CD4+T-bet+, CD4+pSTAT3+ and CD8+T-bet+ T cells in the peripheral blood of natalizumab treated multiple sclerosis patients. Mutations of STAT3 and clinical manifestations of hyper IgE syndromes (Review) Results reveal an elegant mechanism of eNOS regulation by PECAM-1 through signal transducers and activators of transcription 3-mediated transcriptional control of NOSTRIN. Authors believe in order to exclude the association of STAT3 polymorphisms with MS in particular and any other autoimmune disorders in general, we should investigate polymorphisms in more than four regions within the gene. Siltuximab effectively blocks the IL-6/Stat3 signaling pathway in ovarian cancer. Loss of STAT3 activity in lung cancer cells resulted in reduced cell proliferation and apoptosis and combined EGFR and STAT3 loss had additional antitumor effects. The CRE-like site located near the SBE may contribute to the formation of a stable complex of STAT3, HIF-1alpha, and p300/CBP, which leads to maximum transcription of the Hp gene. CCN2/CTGF is identified as a hepatocellular negative acute phase protein which is down-regulated by IL-6 via the STAT3 pathway through interaction on the DNA binding level our findings reveal a novel role for STAT3 in NK cell immunosurveillance by modulating the MICA expression in cancer cells. During dendritic cell differentiation toll-like receptor agonists induce a STAT-3-mediated expression of PD-L1 and favor the development of tolerogenic antigen presenting cells. Extracellular hepatitis C virus core protein activates STAT3 in human monocytes/macrophages/dendritic cells via an IL-6 autocrine pathway. The effects of the site of mutation in the STAT3 domains that are associated with autosomal dominant hyper IgE syndrome are reported. Interleukin-6 induction of toll-like receptor 4 gene expression via signal transducer and activator of transcription 3(STAT3) is one of the main mechanisms underlying insulin resistance in human skeletal muscle Strong activation of Stat3, such as by interleukin (IL)-6 in inflamed tissue, results in release from regulatory T cell suppression, whereas functional suppression is restored upon concurrent activation of Stat1. Common variation in the STAT3 may influence mtDNA copy number. STAT3 activation in colorectal cancer is associated with adverse clinical outcome STAT3 down-regulation resulted in an increase of Survivin/BIRC5 and BCL-xL mRNA in pancreatic neoplasms. activated STAT3 signal may associate with Twist and E-cadherin expression and mediate HCC invasiveness and metastasis. STAT3 phosphorylation is increased in skeletal muscle following intense exercise. Data show that MUC1-C interacts directly with JAK1 and STAT3. mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer ATP-binding membrane cassette transporter A1 and signal transducer and activator of transcription 3 have roles in tristetraprolin-dependent post-transcriptional regulation of inflammatory cytokine mRNA expression by apolipoprotein A-I Data supports activation of a central IL6-STAT3-HIF1A pathway in OCCA. malignant T cells in cutaneous T-cell lymphoma (CTCL) lesions express IL-17 and that this expression is promoted by the Jak3/Stat3 pathway. STAT-3 binds to the NF-kappaB p50/p65 dimers and that the STAT-3/NF-kappaB complexes bind to DNA and activate NF-kappaB-regulated genes inhibition of the inappropriate activation of STAT3/Pim1 axis is a novel, specific, and attractive therapeutic strategy to reverse Pulmonary artery hypertension. Signal transducer and activator of transcription 3 (STAT3) and Suppressor of Cytokine Signaling (SOCS3) balance controls cytotoxicity and IL-10 expression in decidual-like natural killer cell line NK-92. Data show that PrLZ elevated the phosphorylation of Akt and Stat3 and upregulated Bcl-2 expression. Data show that CD5 expression is associated with NFAT2 activity and mildly STAT3 activity, indicating that CD5 controls IL-10 secretion. The purpose of this study was to investigate the possible suppressive or stimulatory role of OSM in the ovarian cancer model of SKOV3 cells, as well as the involvement of the ERK1/2, p38 and STAT3 signaling pathways. CYP3A4 is a highly active AA epoxygenase that promotes Stat3-mediated breast cancer cell growth in part through (+/-)-14,15-EET biosynthesis. IL-6 induction of STAT3 signaling occurred exclusively in the nuclei of satellite cells in response to muscle-lengthening contractions. Finding supports the notion that the combination of inappropriate STAT3 and AP-1 activities drives elevated MMP-1 expression and tissue invasion in colorectal cancer. Data show that ALK inhibitor-induced apoptosis is mediated both by BIM upregulation resulting from inhibition of ERK signaling as well as by survivin downregulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells. The JAK2/STAT3 signaling pathway plays an important role in the angiogenesis of non-small cell lung cancer. JAK1/STAT3 signaling mediates CK-induced apoptosis in U266 cells and also suggest the chemopreventive potential of CK for treatment of multiple myeloma. First report of type I hyper-IgE syndrome (HIES) showing a STAT3 gene mutation and MCNS. Single nucleotide polymorphisms in STAT3 is associated with prostate cancer. STAT3 phosphorylation is an early event in the healing response to muscle injury after repeated biopsy, probably mediated by the autocrine production of IL-6. There was a positive correlation between STAT3 and vimentin expression and a negative correlation between STAT3 and E-cadherin in colon cancer. The novel curcumin analog FLLL32 has biologic activity against osteosarcoma cell lines through inhibition of STAT3 function and expression. STAT3 mediates resistance to MEK inhibitor through microRNA miR-17 STAT3 enhances the proliferation of limbal keratinocytes through a DeltaNp63-dependent mechanism. Suppression of this pathway inhibits cell proliferation with a concomitant increase of cell differentiation. Intracellular apoptotic signals in HHUA cells are constitutively activated and regulated by STAT3-mediated signals. Activation of a pro-survival IL-6/JAK2/STAT3 cascade contributes to cholera toxin-induced GFAP expression. STAT3 signaling pathway plays an important role in the angiogenesis of pancreatic cancer. show that Stat3 signaling enforces MMP7 expression in pancreatic ductal adenocarcinoma cells and that MMP7 deletion limits tumor size and metastasis in mice data describe the involvement of IL-6 transsignaling/Stat3/Socs3 in pancreatic intraepithelial neoplasia progression and pancreatic ductal adenocarcinoma development Constitutively active STAT3 rescued the effects of BMX downregulation, supporting that BMX signals through STAT3 in glioblastoma stem cells (GSCs). Gene silencing of STAT3 leads to cell death by blocking nuclear transfer of STAT3 and STAT3-bound NF-kappaB. chronic lymphocytic leukemic cells express a functional hepatocyte growth factor receptor (c-MET) and hepatocyte growth factor enhanced the viability of these cells through STAT3 phosphorylation Celecoxib inhibits interleukin-6/interleukin-6 receptor-induced JAK2/STAT3 phosphorylation in human hepatocellular carcinoma cells STAT3 plays an integral role in human vascular remodeling and atherosclerosis in a Hyper-IgE syndrome (HIES) cohort patients. STAT3 facilitates NF-kappaB binding to genes that are important for tumor growth while inhibiting its binding to Th-1 immunostimulatory genes in growing tumors, including in tumor-infiltrating immune cells. the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells . LLL12 significantly inhibited STAT3 phosphorylation. CD109 release from the cell surface in human keratinocytes regulates TGF-beta receptor expression, TGF-beta signalling and STAT3 activation. Activation of the signal transducer and activator of transcription 3 pathway up-regulates estrogen receptor-beta expression in lung adenocarcinoma cells Our results suggest that the expression of STAT3 might be an independent prognostic marker for NSCLC patients. signaling in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis (review) inhibition of beta-catenin signaling was dependent on its ability to induce DKK1, in a STAT 3-dependent manner. Inhibition of STAT3 and DKK1 abrogated the ability of IFN-gamma to enhance HIV replication in astrocytes. constitutive activation of STAT3 is an important factor related to carcinogenesis of human soft tissue tumors and is significantly associated with its clinicopathological parameters Suggest a potential role for activated pSTAT3 in lymphatic metastases in thyroid cancer. Results show that STAT3 has critical roles throughout the course of PDAC pathogenesis. our findings suggest that SOCS3 inactivation by promoter hypermethylation is mutually exclusive to EGFR activation in gliomas and preferentially promotes glioma cell invasion through STAT3 and FAK activation. Studies indicate that Stat3 signals are pivotal to the proliferation and differentiation of neural stem cells. The regulatory effect of the intronic miRNA on eNOS gene expression was associated with miRNA polymorphisms, and mediated through inhibition of STAT3 signaling in ECs. The data reveal endosomes as central to the genesis, course and outcome of STAT3 signal transduction and transcription. identified a significant association between STAT3 polymorphism and asthma susceptibility in atopic asthma whereas no such association was observed in the non-atopic asthma group Results indicate STAT3 nuclear import is dependent on the function of importin-beta1 Intratumoral administration of STAT3 transgene-depleted dendritic cells (DC)markedly inhibits colon carcinoma growth of injected and nontreated remote tumors; STAT3-deficient DCs activate T helper (Th)1 cells and resist cancer-derived inhibitory factors. Data show that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+CD24- breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. HIV-1-infected/activated monocyte-derived macrophages induces neural progenitor cell astrogliogenesis through the STAT3 pathway. the loss of ARHI expression in the majority of ovarian cancers may result in the upregulation of Stat3 and FAK activity, and thereby contribute to oncogenesis. The inhibitory effect of RNA interference on STAT3 expression in liver cancer cell line SMMC7721 TRP4 can effectively induce the activation of both NF-kappaB and IL6/STAT3 signaling pathways in the pattern similar to that of classical cytokine STAT3 and beta-catenin signaling pathway may affect GSK-3beta expression in hepatocellular carcinoma. STAT3 gene polymorphism (rs4769793) was associated with the susceptibility as well as poor differentiation and parametrial invasion of cervical cancer in Chinese women Leptin promotes endometrial cancer growth and invasiveness by activating STAT3 and ERK1/2 signaling pathways. Excessive IL-22 can be found in the hepatocellular carcinoma microenvironment, leading to tumor growth, inhibition of apoptosis, and promotion of metastasis due to STAT3 activation. Data demonstrate a role of STAT3 in regulation of mdr1 gene expression in myeloid leukemia and suggest that STAT3 may be a promising therapeutic target for overcoming MDR resistance in myeloid leukemia. The inhibited viability of HeLa cells caused by knockdown of c-SRC is associated with the decreased content of p-STAT3 protein. In the tumors The prognostic significance of IL-8 expression and its correlation with p-STAT-3 and VEGF implicates this novel signaling pathway in astroglial tumors progression providing new targets for effective immunotherapy. novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC study demonstrates that the Src/Stat3 and C/EBP signaling pathways positively regulate the expression of the Jab1 oncogene; results show that Stat3 and LAP2 (C/EBP-beta2) are the two major transcription factors that contribute to Jab1 overexpression [...] TRIM8 modulates translocation of phosphorylated STAT3 into the nucleus through interaction with Hsp90beta and consequently regulates transcription of Nanog in embryonic stem cells. 12% of inflammatory hepatocellular adenoma subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49) We propose that nuclear CD44/acetylated-STAT3 performs an unexpected tumour-progressing function by enhancing cell outgrowth into structures where cells with properties of cancer stem cells can be generated from differentiated somatic cells. CK2 inhibitors enhance the radiosensitivity of human non-small cell lung cancer cells through inhibition of stat3 activation a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor. Significant increases in the phosphorylation levels of transcriptional regulation of STAT3-downstream target molecules were observed in colorectal adenoma tissue. immunohistochemical investigation of variables involved in expression of STAT3 (alongside Bak and Bcl-xL) in endometrioid adenocarcinoma tissue: STAT3 is abundantly expressed in nuclei in some patients; expression in ERalpha +/- tissues CD24 was found to be a functional liver tumor-initiating cells (T-IC) marker that drives T-IC genesis through STAT3-mediated NANOG regulation. STAT3 is a modifier gene of cystic fibrosis disease. Constitutively activated STAT3 induces vascular endothelial growth factor production by chronic lymphocytic leukemia cells and chronic lymphocytic leukemia cells derive a survival advantage from endothelial cells via cell-to-cell contact. pancreatic Stat3 has a role in ER-mediated suppression of lipid synthesis JAK2V617F allele burden was higher in polycythemia vera (PV) and primary myelofibrosis (PMF) patients compared with low allele burden in essential thrombocythemia (ET) and early PMF; higher phosphorylation of STAT5 and STAT3 in JAK2V617F positive group Glucocorticoids enhance Th17/Th1 imbalance and signal transducer and activator of transcription 3 expression in systemic lupus erythematosus patients. Interplay between SIN3A and STAT3 mediates chromatin conformational changes and GFAP expression during cellular differentiation.( PLTP regulates STAT3 and NFkappaB in differentiated THP1 cells and human monocyte-derived macrophages. Cells transformed by the p110alpha-H1047R mutant of PI3K show increased tyrosine phosphorylation of Stat3. reduced IL-10-mediated phosphorylation of STAT3 in hyper-IgE syndrome patients with mutations in the SH2 domain of STAT3 The data suggested that IL-17A can upregulate keratin-17 expression in keratinocytes in a dose-dependent manner through STAT1- and STAT3-dependent mechanisms. STAT3 is more frequently expressed in non-GCB DLBCL than that in GCB subtype, and its strong nuclear expression is correlated with poor OS in DLBCL. data demonstrate that constitutive activation of STAT3 in Sezary syndrome is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis These results indicate that STAT3 is essential for VEGF-A-induced lymphatic endothelial cell (LEC) migration and tube formation and that STAT3 regulates LEC functions. Epigallocatechin-3-gallate reduces expression of VEGF in gastric cancer cells through the inhibition of Stat3 activity. This is the first evidence that PPAR-gamma activation can counteract STAT-3-dependent escape pathways to IFN-beta-induced growth inhibition through cell cycle perturbation and increased autophagic death in pancreatic cancer cells. The M4 adenovirus could specifically deplete constitutive and inducible STAT3 and phosphorylated STAT3 proteins in ovarian cancer cells. Deregulated expression of pSTAT3 and SOCS3 might possess potential roles in the development and progression of human cutaneous melanoma. Dehydroepiandrosterone reverses pulmonary hypertension in part by inhibiting the Src/STAT3 pathway. STAT3 activities of human papillary thyroid cancer tissues are significantly lower than those of surrounding normal thyroid tissues. ALDH(+)/CD133(+) cells expressed higher levels of the active phosphorylated form of STAT3 than either ALDH(-)/CD133(-) or unfractionated colon cancer cells. Glioblastoma-derived IL-6 is responsible for the observed suppression of Langerhans cell differentiation from CD34(+) precursors but appears to exert this effect in a STAT3 and Raf-1 independent fashion CD5 costimulation induces more Th17 cells that produce higher amounts of IL-17, which is preceded by prolonged activation of signal transducer and activator of transcription 3 (STAT3). Both STAT3 and NFkappaB are required for the cytokine-induced expression of fascin in cancer cells. data point toward a pivotal role for an autocrine positive feedback loop involving IL-21 and consequent persistent STAT3 activation in the pathogenesis of Sezary syndrome both rs6503691 T allele and CT/TT genotypes, but not rs4796793 C/G in STAT3, are associated with a significantly increased risk of dilated cardiomyopathy polymorphisms in the STAT3 gene may have a protective role in the development of non-small cell lung cancer (NSCLC), particular of stage III/IV NSCLC NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression. Our results demonstrate that melatonin receptor/Galpha(16) coupling is capable of triggering the production of cytokines including IL-6, and this autocrine loop may account for the subsequent STAT3 phosphorylation at Tyr(705) HDAC1 and HDAC2 differentially modulate STAT activity in response to IFNalpha2: while they are required for the induction of ISGF3-responsive genes, they impair the transcription of STAT3-dependent genes. Studies indicate that in Th17 cells, activated STAT3 by IL-6 positively regulates H3K4me3 deposition in the Il17 locus. STAT3 and NF-kappaB pathways co-operate in IgA production, with soluble CD40L rapidly activating the NF-kappaB pathway, probably rendering STAT3 probably more reactive to IL-10 signalling. STAT3 plays an important role in regulation of tumor growth, invasion, and angiogenesis, which could be act by reducing MMP-7 expression in pancreatic cancer cells. IL-6- and TNFalpha-induced TNFR2 expression in colon cancer cells is mediated primarily by STAT3 and provide evidence that TNFR2 may contribute to the tumor-promoting roles of STAT3. a novel pathway in the melanocyte lineage, linking FGF2-STAT3 signaling to increased PAX3 transcription. The overall results point towards a novel ability of HDM2 in regulating HIF-1alpha and p-STAT3 levels even in normoxic conditions that eventually lead to an up-regulation of VEGF expression. STAT3 alternative splicing modulation yields an antitumorigenic potential. Phosphorylated Stat3 is associated with neoplastic transformation in patients with colitis. studied the effect of decreased STAT3 signaling on the B-cell compartment in hyper-IGE syndrome with heterozygous STAT3 mutations STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin. These findings illustrated the biological significance of JAK2/STAT3 signalling in colorectal cancer cell apoptosis. Elp2 and STAT-3 mediate, at least in part, the stimulation of Hsp70 expression by 4PBA. The effects of STAT3 inhibition in colon cancer stem-like cells were examined. A 24h exposure of B lymphocytes with NAC is sufficient to show strong inhibition of STAT3 phosphorylation. pSTAT3 was abnormally expressed in pancreatic adenocarcinoma & related to tumor size, TNM staging & lymphatic metastasis. It may promote tumor angiogenesis via upregulating VEGF & enhance lymphatic metastasis via VEGF-C. a new biological activity for CUEDC2 as the regulator of JAK1/STAT3 signaling and the mechanism by which SOCS3 has been linked to suppression of the JAK/STAT pathway the expression of miR-125b is regulated by STAT3 at the level of transcription. STAT3 binds to the promoter region of miR-125b in vitro and serves as a transactivator. This study supports the association between STAT3 and an increase in multiple sclerosis risk. antiproliferative effect of SOCS-1 was attributable not only to the inhibition of STAT3 but also to that of p38 MAPK activity Enhanced growth inhibition in hepatoma cells treated with both NSC 74859 and cetuximab suggests that cetuximab resistance is probably mediated via STAT3. Constitutive activation of signal transducers and activators of transcription 3 correlates with better prognosis, cell proliferation and hypoxia-inducible factor-1alpha in human gastric cancer. cell-cell interactions of M2 macrophage/microglial cells with lymphoma cells induced Stat3 activation may provide novel insights into PCNSL pathogenesis Stat3 and its target genes were overactivated and/or overexpressed in drug resistant cells STAT3 was required for proper induction of IL6 by NF-kappaB Increased activity of Stat3 and overexpression of PLK1 promote survival and proliferation of esophageal squamous cell carcinoma cells in culture and in mice. A novel dendritic cell(DC) progenitor regulatory pathway in which PGE(2) signaling through EP1/EP3 receptors regulates Flt3 expression and downstream STAT3 activation and survivin expression, required for optimal progenitor survival and differentiation. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses. Data show that inhibitors of Stat3, IGF-IR and Rho GTPase were the most promising therapeutic agents for ovarian cancer. Acyl derivatives of boswellic acids are inhibitors of NF-kappaB and STATs STAT3 and STAT5 gene SNPs may be prognostic of leukemia. Activated Stat3 may regulate the migration of breast cancer cells through the regulation of ATX. Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-kappaB and STAT3 pathways. nuclear pSTAT3 might play a role as a tumor suppressor in high-grade salivary gland carcinomas skeletal myoblasts undergo apoptosis under oxidant stress in a time-dependent manner and preconditioning of skeletal myoblasts significantly prevented their apoptosis via IL-11/STAT3 signaling. Using knockdown of AKT & STAT3, studied the effects of IL-17/AKT signaling in HCC, resulting in IL-6 production, which in turn activated JAK2/STAT3 signaling and subsequently up-regulated its downstream targets IL-8, MMP2, and VEGF. Our findings establish a new role for the FGFR4-G388R polymorphism in pituitary oncogenesis, providing a rationale for targeting Src and STAT3 in the personalized treatment of associated disorders. Data show that ectopic expression of STAT3 abolished the apoptotic effect of dovitinib, indicating that STAT3 is indispensable in mediating the effect of dovitinib in hepatocellular carcinoma (HCC). TGF-beta1, IFN-gamma, IL-6, and IL-22 induce podoplanin-expression in keratinocytes via STAT3 pathway. STAT3 activation is critical for Varicella-zoster virus replication via a survivin-dependent mechanism. tumor cell-derived IL-6 induced gp130 and IL-6R-dependent activation of STAT3, leading to reduced caspase-3 activation and apoptosis. Heparanase enhances the phosphorylation of STAT3 and STAT5b but not STAT5a in head and neck cancers. STAT3 ''A'' risk allele is associated with increased cellular STAT3 activation and upregulation of pathways that promote recruitment of CXCR2+ neutrophils to the gut. Data suggest that nitidine chloride is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor. STAT3 genetic polymorphism is associated with the susceptibility to BD. the roles of STAT3 in colorectal cancer epithelial-mesenchymal transition and in STAT3-induced down-regulation of E-cadherin Taken together our studies further reveal that STAT3 plays a key role in SPARC induced G2/M arrest in medulloblastoma cells. Our results suggest that p-STAT3 is an important factor during carcinogenesis and metastasis of lung carcinoma. Persistent activation of STAT3 is a unifying hallmark of a majority of solid malignancies--[REVIEW} Pien Tze Huang promotes cancer cell apoptosis and inhibition of proliferation via suppression of STAT3 pathway in colorectal neoplasms. peripheral blood lymphocytes (PBLs) of ovarian cancer patients showed lower JAK3, CD3-zeta molecules expression levels, as well as lower STAT3 and CD3-zeta phosphorylation levels than cells of control. phospho-Ser727 determines the duration of STAT3 activity largely through TC45. STAT3-mediated IL-21 signaling can supplement partial t-cell receptor signaling caused by the lack of CD8 association. these results suggest a previously unknown Stat3-Skp2 molecular network controlling cervical carcinoma development. The high expression level of Stat3 and Cyclin D1 protein in laryngeal squamous cell carcinoma was correlated with the clinical stage, tumor differentiation and lymph node metastases. Data indicate that the rs744166 STAT3 variant in homozygous form showed a significantly elevated odds ratio of 1.483 for the development of ulcerative colitis (UC) but conferred no significant risk of Crohn's disease (CD). Data show that IL-6 treatment increased expression of phosphorylation of signal transducer and activator of transcription 3 (STAT3) and Pim-1 kinase. Findings show that multiple signaling events impinge on Stat3 and that 14-3-3zeta serves as an essential coordinator for different pathways to regulate Stat3 activation and function in multiple myeloma cells. Increased STAT3 and decreased cyclin D1 protein levels may contribute to the recurrence of astrocytic tumours. Increased Phospho STAT3 is associated with progression of esophageal squamous cell carcinoma. The specific knockdown of Stat3 by RNA interference strongly inhibited the motile and invasion activity of tumour cells. Piwil2 plays a role in anti-apoptosis in tumor cells possessing P53 as a positive regulator of STAT3 signaling pathway. SOCS-3 gene induction requires c-Jun, signal transducer and activator of transcription 3, and specificity protein 3 transcription factors. a model of CagA-directed REG3gamma expression in gastric epithelial cells via activation of the IL-11/gp130/STAT3 pathway Thymic stromal lymphopoietin may upregulate c-Myc expression through activation of STAT3 pathway, thereby inducing trophoblast proliferation. JAK2/STAT3 signaling operates independent of known driver mutations in non-small cell lung carcinoma and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations. This data suggest that STAT3 activation regulates several pathways in human lung fibroblasts associated with normal wound healing, whereas aberrant STAT3 signaling plays a critical role in idiopathic pulmonary fibrosis pathogenesis. The STAT3 pathway plays a key role in mediating CSC properties in ATC-CD133+ cells. A subset of genes uniquely regulated by STAT3 in response to leptin was identified in cells exposed to Entamoeba histolytica. Prostacyclin receptor-dependent inhibition of human erythroleukemia cell differentiation is STAT3-dependent STAT3 plays a key role not only in cardiac protection but also in the control of cardiac-related inflammation. Review. Targeting both Sp1 and Stat3 is a potential preventive and therapeutic strategy for pancreatic cancer. the possible role of MMP-2/alpha5beta1 interaction in the regulation of alpha5beta1-mediated IL-6/Stat3 signaling activation The STAT3 silencing by siRNA inhibited the proliferation of AGS human gastric cancer cells through G1 cell cycle arrest, decreased levels of immune-suppressive cytokines, and increased levels of immune-activating cytokines. Data suggest that TSLP might downregulate NME1 expression via STAT3 signaling pathway, affecting TIMP1 expression in influencing trophoblast invasion. Celastrol suppresses growth and induces apoptosis of human hepatocellular carcinoma through the modulation of STAT3/JAK2 signaling cascade in vitro and in vivo The role of Phospho- STAT3 as an important independent prognostic marker in node-positive breast cancer patients. the GG genotype might confer increased resistance to standard chemotherapy in acute myeloid leukemia (AML) in the Chinese population Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA Both STATs 1 and 3 were highly expressed in cerebral arteriovenous malformation, mainly in the endothelium of AVM blood vessels and perivascular infiltrating inflammatory cells within the nidus. the expression of phosphorylated STAT3 (pSTAT3) in non-small cell lung cancer PTPMeg2 is an important phosphatase for the dephosphorylation of STAT3. Leukotriene B4 receptor-2 promotes invasiveness and metastasis of ovarian cancer cells through signal transducer and activator of transcription 3 (STAT3)-dependent up-regulation of matrix metalloproteinase 2 EGF-mediated CYR61 upregulation in HES cells involves STAT3 and is counter-regulated by the EGFR/MAPK/ERK pathway. RNAi to diminish expression of ErbB receptors and AP-1 proteins strongly suggested that STAT3 established a balance that maintains the appropriate set of AP-1 proteins and participates in a complex network for regulating keratinocyte differentiation. Activator of transcription 3 (STAT3) pathway is implicated in the production of various cytokines in patients with primary Sjogren's syndrome. Ser727 phosphorylation on STAT3 is not necessarily a secondary event after Tyr705 phosphorylation and suggest that it has a role in the regulation of cell survival activity and nuclear translocation of STAT3 in melanocytic cells. Identify STAT3 as a key molecule for the proliferative response of SMC and neointima formation. Chrysanthemum indicum extract suppressed constitutive STAT3 activation in parallel with the inhibition of constitutive JAK1 and JAK2 activation in human prostate carcinoma cells. Results show that accumulation of pSTAT3-Tyr705 promotes EGFR L858R mutant cell death, thereby confirming the existence of a STAT3-dependent pro-apoptotic pathway in these lung cancer cells. STAT3 might be correlated with tumor differentiation, and its elevated expression may be an adverse prognostic indicator for patients with NSCLC. Pretreatment of tumor cells with STAT3 specific inhibitors or knocking down of STAT3 by SiRNA makes the tumor cell more susceptible to apoptosis and dendritic cell mediated inhibition of both CD24 and HER-2/neu Expression of pSTAT3 correlates with Her-2 status and CAIX expression and is associated with tumor progression and worse outcome in esophageal cancer Stage IV melanoma patients without CNS metastasis treated with p-STAT3 inhibitors in efficacy studies should be stratified based on tumor expression of p-STAT3. IL-6 increased IL-21 production by human CD4(+) T cells driving STAT3-dependent plasma cell differentiation. GRIM-19 expression is closely correlated with histological grading and p-STAT3 in hepatocellular carcinoma PLD acts as an important regulator in Bcl-2 expression by activating STAT3 involving the phosphorylation of Ser727 through the PLA(2)/G(i)/ERK1/2, RhoA/ROCK/p38 MAPK, and Rac1/p38 MAPK pathways. The anticancer effects of celecoxib on nasopharyngeal carcinoma cell lines results from inducing apoptosis and cell cycle arrest, which may be partly mediated through the STAT3 pathway. Abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-alpha production in the presence of suppressive patient plasma. model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein present study suggests that IL-6 inhibits senescence but promotes the survival and proliferation of tumor cells exposed to DNA damage through the activation of the JAK1-STAT3 signaling pathway Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. findings show that Stat3-induced stem cell expansion plays a critical role in the unique clinical progression of invasive bladder cancer through the CIS pathway The authors have identified IL-6-mediated STAT-3 signalling in CD4 T cells during the earliest clinical phase of rheumatoid arthritis. High phospho-STAT3 expression is associated with mucosal relapse in ulcerative colitis. Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3. Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. STAT3 signaling pathway may correlate with epigenetic aberrance during gastrocarcinogenesis Dynamin II function is required for EGF-mediated Stat3 activation but not Erk1/2 phosphorylation these results demonstrate that in results demonstrate that in human endothelial cells resistin up-regulates SOCS3 expression and activates STAT3 transcription factor. STAT3 mutations correlated with hyper-IgE syndrome lead to blockage of IL-6/STAT3 signalling pathway. results suggest that Notch1/STAT3/Twist signaling axis is involved in progression of human gastric cancer and modulation of this cascade has potential for the targeted combination therapy The SH2 dimerization and activation domain of STAT3 is frequently mutated in patients with large granular lymphocytic leukemia; these findings suggest that aberrant STAT3 signaling underlies the pathogenesis of this disease. present study demonstrates that Ang II induces angiogenic factors production partly via AT1/ JAK2/STAT3/SOCS3 signaling pathway in MHCC97H cells Interleukin 11 regulates endometrial cancer cell adhesion and migration processes via phosphorylation of STAT3 Demonstrate that S1PR1-STAT3 signalling enables myeloid cells to intravasate, prime the distant organ microenvironment and mediate sustained proliferation and survival of their own and other stromal cells at future metastatic sites. beta-catenin pathway regulates miR-21 expression in umbilical vein endothelial cells and glioma cells. This is STAT3 dependent. STAT3 and BLIMP-1 constitute an incoherent feed-forward loop downstream of IL-21 that can coordinate microRNA with mRNA expression during plasma cell differentiation. STAT3 was inactivated in most LMS cases. Interleukin-27 and interleukin-12 augment activation of distinct cord blood natural killer cells responses via STAT3 pathways. STAT1 expression is upregulated by nuclear EGFR and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. Reduction of miR-21 repressed human telomerase reverse transcriptase expression in a STAT3-dependent fashion, subsequently inhibiting glioblastoma cell growth. STAT3 dimerization at the receptor are essential for the dynamics of early pathway activation. Data show that LIF through STAT3 negatively regulates Th2 differentiation. endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The altered JAK2 induced STATs response in human failing cardiomyocytes may be of relevance for the progression of cardiac dysfunction in heart failure. Modulation of STAT-3 in CD4+ T cells affects the differentiation of Th17 cells and Treg cells in patients with rheumatoid arthritis. STAT3 was activated and that the activation could be blocked by an IL-6-neutralizing antibody. Persistent activated STAT3 colocalizes with elevated expression of S1PR1, a G-protein-coupled receptor for sphingosine-1-phosphate (S1P), in the tumor cells of the activated B cell-like subtype of diffuse large B-cell lymphoma. previously unknown STAT3-USP7-P53 molecular network controlling colon cancer development Targeting Stat3 or Smad7 for knockdown results in resensitization of TGF-beta's cytostatic regulation in vivo. Recurrent bacterial skin and respiratory tract infections were consistently observed in STAT-3 deficient patients. The findings suggest that variants in the STAT3 gene may contribute differentially to susceptibility to rheumatoid arthritis in seropositive and in seronegative patients. STAT3 is aberrantly hypomethylated and overexpressed in hematopoietic stem cells of myelodysplastic syndromes patients. results provide evidence that CD24 regulates STAT3 and FAK activity and suggest an important role of Src in this process. STAT3 protein interacts with Class O Forkhead transcription factors in the cytoplasm and regulates nuclear/cytoplasmic localization of FoxO1 and FoxO3a proteins in CD4(+) T cells. HIV-1 interaction with dendritic cells modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells. H. pylori induced inflammation up-regulate Hath1 expression via interleukin-8/STAT3 phosphorylation while suppressing Hes1, which provides a novel molecular connection between a H. pylori infection and intestinal metaplasia. analysis of the positive link between STAT3 activation and Th17 cell infiltration to the lesional skin in vitiligo vulgaris Stat3 forms a multiprotein complex with Rac1 and PKC in an hypoxia-reoxygenation-dependent manner. results highlight STAT3beta as a significant transcriptional regulator in its own right, with additional actions to cross-regulate STAT3alpha phosphorylation and nuclear retention after cytokine stimulation Overview of the role of STAT3 in regulating cellular responses that may contribute to or inhibit pro-fibrotic processes in idiopathic pulmonary fibrosis. [Review Article] IL-22 up-regulates K17 expression in keratinocytes in a dose-dependent manner through STAT3- and ERK1/2-dependent mechanisms. Together these results suggest that the inhibitory effect of OSM on TGF-beta1-induced CTGF mRNA expression is mainly driven by STAT3, thereby providing a signaling mechanism whereby OSM may contribute to tubulointerstitial protection. Targeting STAT3 using a specific inhibitor may be a useful cancer treatment approach, with the potential for a broad clinical impact. Migfilin positively modulates the expression and activity of epidermal growth factor receptor, and Migfilin-mediated migration and invasion depend on epidermal growth factor receptor-induced PLC-gamma and STAT3-signaling pathways. vSOCS inhibits IFN-alpha-induced Stat1/Stat3 signaling. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. In the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. MLS-2438 inhibits viability and induces apoptosis of human melanoma cells associated with inhibition of STAT3 and Akt signaling. After the cancer cells were incubated with the synthesized PLGA nanocomplexes, PLGA-PEI-TAX-S3SI suppressed Stat3 expression and induced more cellular apoptosis in A549 and A549/T12 cells compared with PLGA-PEI-TAX. Acyloxy nitroso compounds inhibit LIF signaling in endothelial cells and cardiac myocytes, showing that STAT3 signaling is redox-sensitive STAT3 is involved in sperm functions. the intracellular interaction of IL-32alpha with PKCepsilon and STAT3 promotes STAT3 binding to the IL-6 promoter by enforcing STAT3 phosphorylation, which results in increased production of IL-6. Physiological concentrations of hydrogen peroxide activate hepcidin transcription through signal transducer and activator of transcription 3 protein. The expression levels of STAT3, P-STAT3, and VEGF-C were higher in small cell lung cancer than in normal tissue; STAT3 and VEGF-C play important roles in the development of small cell lung cancers The results of this study suggested that the STAT3-mediated astrogliosis protects myelin development in neonatal brain injury STAT3 and STAT5 may function through the IL-6 and IL-2 pathways to play a role in the imbalance of Th17/Treg in NP. Consequently, p27 of hepatitis delta virus activated the signal transducer and activator of transcription-3 (STAT-3) and the nuclear factor kappa B (NF-kappaB) via the oxidative stress pathway. CSE1L- and inhibitor of DNA binding-3 (ID3)-overexpression was associated with the diagnosis of BL and signal transduction and transcription-3 (STAT3) with DLBCL (P<0.001 for all markers). All three markers were associated with patient outcome in DLBCL apoptosis induced by knockdown of uPAR and MMP-9 is mediated by inactivation of EGFR/STAT3 signaling in medulloblastoma JAK2 and STAT3 activation is not essential for CCL3, CCL5 or CCL8 induced chemotaxis. GABA may inhibit the growth of cholangiocarcinoma QBC939 cells through the GABAB receptor, and the anti-cancer effects may be partly mediated via the JAK/STAT3 pathway. Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or DeltaNp63alpha. Uropathogenic Escherichia coli strain-infection decreases STAT3 phosphorylation in 5637 cells. postseptic CD4 T cells are primed toward IL-17 production via increased STAT3-mediated gene transcription, which may contribute to the immunopathology of a secondary viral infection. The results implicated excessive STAT3 signaling in the development of skeletal muscle insulin resistance in type 2 diabetes. a previously unknown link between Wnt3a-mediated activation of STAT3 and cell survival STAT3 polymorphism can be a predictive marker for treatment with IFN-alpha for patients with metastatic renal cell carcinoma. STAT3 rs1053023 was positively associated with idiopathic recurrent miscarriage in both Bahraini and Tunisian women. STAT3 activation is directly integrated with the receptor tyrosine kinase-GIV-G protein signaling axis. These results provide evidence that activated STAT-1 and STAT-3 regulate VEGF expression indirectly, by modulating HIF-1alpha activity. Results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors High STAT3 phosphorylation is associated with reduced anti-EGFR-based therapy in patients with metastatic colorectal cancer Report mechanism of autophagy control that involves STAT3 and PKR as interacting partners. STAT3 is critical for cancer stem cells survival. APE1/Ref-1 regulates STAT3 transcriptional activity and APE1/Ref-1-STAT3 dual-targeting effectively inhibits pancreatic cancer cell survival. these findings revealed a novel functional link between C/EBPbeta and STAT3 that is a critical regulator of endometrial differentiation in women. these results indicate that thrombin might activate c-Src to induce JAK2 activation, which in turn, causes STAT3 activation, and finally induces CCN2 expression in human lung fibroblasts. Using two renal cellular models&SOCS-3 siRNA knockdown,we studied SOCS-3 effects on oncostatin M-induced STAT activation, differentiation and proliferation.SOCS-3 knockdown resulted in enhanced pSTAT1/3 phosphorylation & epithelial diff'n. Data indicate that knockdown of HDAC8 resulted in the increased expression of SOCS1 and SOCS3, and overexpression of SOCS1 and SOCS3 significantly inhibited cell growth and suppressed JAK2/STAT signaling. GRIM-19 inhibits the STAT3 signaling pathway and sensitizes gastric cancer cells to radiation. CCR1-mediated STAT3 tyrosine phosphorylation and CXCL8 expression in THP-1 macrophage-like cells involve pertussis toxin-insensitive Ga14/16 signaling and IL-6 release. Our results suggest for the first time that the STAT3 gene might be involved in PsA but not in Behcet's disease predisposition. These results suggest a critical association between altered expression of STAT-3 and STAT-5 with SOCS-1 and indicate its potential role as a negative regulator independent of JAK-STAT pathway in tumorigenic transformation of prostate tissue. STAT3 is not crucial for the control of basal cell proliferation and survival of lung carcinoma cells but modulates susceptibility to DNA damaging chemotherapeutics by regulation of intrinsic pro-survival pathways. Leptin/STAT3 signaling is a novel pathway for the up-regulation of hTERT expression in breast cancer cells. HBx activates the Twist promoter by activating STAT3 and promotes epithelium-mesenchymal transition occurrence in liver cells. TCPTP deficiency in human breast cancer cell lines enhances Src family PTKs and STAT3 signaling. The dynamic genome-wide transcriptional responses were nearly identical at early time points following stimulation (when STAT3 is active in response to both IL-6 and IL-10) but divergent at later times (when STAT3 is active only in response to IL-10). STAT3 regulates the transcription and expression of Oct-1 by directly targeting its promoter. this is the first study showing the crucial role of NF-kappaB/Stat3 nuclear association in IR-induced ICAM-1 regulation and implies that targeting NF-kappaB/Stat3 interaction may have future therapeutic significance in glioma treatment. ubiquitin ligase TRAF6 negatively regulates the JAK-STAT signaling pathway by binding to STAT3 and mediating its ubiquitination The functions of TSLP in asthmatic airway remodelling were performed through STAT3 signalling pathway. rs1053023, more so than the STAT3 rs1053004 or JAK2 rs2230724 polymorphisms, is associated with RSM risk. We were able to confirm the presence of STAT3 mutations in large granular lymphocytic leukemia in a high frequency of 72.7%. REVIEW: potential/putative role of STAT3 signaling in nasopharyngeal carcinoma pathogenesis and anti-STAT3 targeting as a therapeutic and possible prevention strategy for NPC STAT3 and EIF2AK2 interact and have roles in controlling fatty acid-induced autophagy interaction between STAT3 and HO-1 abrogates STAT3 activation, and in this way, HO-1 induction represses AR activity, affecting PCa cells tumorigenicity. The present study investigates the involvement of the IL-6 family of cytokines, activation of the transcription factor STAT3 and the role of SOCS3 in regulating excitotoxic neuronal death. Leptin increases HER2 levels by inducing a STAT3-mediated Hsp90 expression in breast cancer cells. examined Stat3 and Stat5 activation patterns in resting and ligand-stimulated primary samples from pediatric patients with acute myeloid leukemia Xanthohumol is a potent antineoplastic chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition. High DARPP32/STAT3, DARPP32/STAT5B, and STAT5B/STAT3 ratios were associated with longer patient progression free survival. Data indicate that active cruzipain completely abrogated the STAT3 phosphorylation and enzymatically cleaved gp130 ectodomain. These data demonstrate a nontranscriptional activity of STAT3 that facilitates a crosstalk between proinflammatory cytokine and hemostasis/thrombosis signals in platelets. import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain Data indicate that tocilizumab enhanced the interferon-induced phosphorylation of STAT1 and inhibited SOCS3 expression and the phosphorylation of both STAT3 and ERK. the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells Activation of STAT3 is associated with glioblastoma multiforme. IL-6 trans-signaling-STAT3 pathway may have an integral role in hypertrophic scar pathogenesis. our results suggest that STAT3 exon 21 mutation is rare in most human cancers reducing EGFR activity strongly reduced pSTAT3 in vivo Upregulation of Stat3 is associated with gastric adenocarcinogenesis. Malignant pheochromocytoma overexpress HSP90 and STAT3. The present study identifies STAT3 as an important signaling molecule interacting with CD44 and demonstrates the essential role of CD44-STAT3 signaling in breast cancer invasion RAD001 might have the capacity to induce megakaryocytic differentiation through the up-regulation of STAT3 signalling Stat3 inhibits WTX expression through up-regulation of micro RNA-370 in Wilms tumor. The depletion of STAT3 inhibited the ability of cells to migrate and invade, and impaired the cellular cytoskeleton mainly microtubules show that these events can be at least in part attributed to the STAT3/Survivin pathway Inhibition of STAT3 activation abolished the wound fluid response, showing that STAT3 plays an important role in the wound healing response. C-reactive protein expression and STAT3 activation are reduced in docosahexaenoic acid and eicosapentaenoic treated HepG2 cells. STAT3 activation was correlated with aggressive behavior of hepatocellular carcinoma and may be mediated via tumor-associated macrophage Suggest that CCK2R-mediated COX-2 up-regulation via JAK2/STAT3/PI3K/Akt pathway is involved in the proliferative effect of gastrin on human gastric cancer cells. Data indicate that galectin-4 elicits tumor promotion in vitro and in vivo through activation of IL-6/NF-kappaB/STAT3 signaling. SNPs appear to predispose the host with hepatitis B virus mutations to hepatocarcinogenesis. Tumor-derived mutations in the gene associated with retinoid interferon-induced mortality (GRIM-19) disrupt its anti-signal transducer and activator of transcription 3 (STAT3) activity and promote oncogenesis a novel STAT3 non-consensus TFBS at nt -75/-66 downstream of the NF-kappaB RE in the SAA1 promoter region that is required for NF-kappaB p65 and STAT3 to activate SAA1 transcription NF-kappaB and STAT3 are positively associated and synergistically contribute to the metastatic potential of gastric cancer cells. Blood CD4+CD45RO+CXCR5+ T cells are decreased but partially functional in signal transducer and activator of transcription 3 deficiency. stimulatory effect of ADSC conditioned media or IL-6 was accomplished through activation of both STAT3 and MAP kinse signaling pathways None of the single nucleotide polymorphisms of either TYK2 or STAT3 was statistically associated with the susceptibility to CD in our local population (P > 0.05). ECHS1 specifically represses STAT3 activity and negatively regulates the expression of several target genes of STAT3 through inhibiting STAT3 phosphorylation. STAT3 induces PTTG expression to facilitate tumor growth and metastasis. Our data demonstrate that STAT3 is critical in IL-17-induced survival of fibroblast-like synoviocytes from rheumatoid arthritis patients. Data indicate that the mode of binding that is similar to that known for the STAT3 core phosphorylated at Y705. overexpression of miR-155 inhibited SOCS1expression, elevated STAT3 expression, and promoted hep-2 cells growth, migration and invasion. Phospho-STAT3 is a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. The tumor suppressive function of arginase-I in both infiltrating and circulating myeloid-derived suppressor cells is a downstream target of activated STAT3. Suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1. Interactions between M2 macrophages and endometrial stromal cells via Stat3 activation may play an important role in the development of endometriosis. HBx upregulates the Bax/Bcl-2 ratio by activating the JAK2/STAT3 signaling pathway. antibody behaves like a potent non-competitive inhibitor blocking IL-21 induced STAT3 phosphorylation for a long period of time. These results may help with the translation of preclinical information and dose selection towards ATR-107 clinical efficacy STAT3-mediated coincidence detection regulates noncanonical immediate early gene induction. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. metformin suppresses STAT3 activation via LKB1-AMPK-mTOR-independent but ROS-related and autocrine IL-6 production-related pathways. Thus, metformin helps to overcome tumor drug resistance by targeting STAT3. Data indicate that STAT3 physically interacted with progesterone receptor (PR)-A, which is known to be important for uterine development and function, but not with PR-B. Data suggest that inhibition of the JAK/STAT3 signal transduction could be a promising therapeutic target for high-risk pediatric solid tumors. alantolactone-induced apoptosis was found to be associated with GSH depletion, inhibition of STAT3 activation, ROS generation, mitochondrial transmembrane potential dissipation, and increased Bax/Bcl-2 ratio and caspase-3 activation siRNA-mediated knockdown of DAPK1 attenuated the curcumin-induced inhibition of STAT3 and NF-kappaB. Moreover, DAPK1 suppression diminished curcumin-induced caspase-3 activation. Knocking down BV8 in human myeloid leukemia cells inhibits STAT3 activity and expression of STAT3 downstream angiogenic and pro-proliferation/survival genes. the influence of STAT3 on the IL-17A/IFN-gamma -mediated RNase 7 induction HCMV activated the IL-6-JAK-STAT3 pathway in PHH and HepG2 cells STAT3 mutations are frequent in CD30 positive T-cell lymphomas and T-cell large granular lymphocytic leukemia. Androgen-STAT3 activation may contribute to gender disparity in human simply renal cysts. STAT3 directly bound to the STAT3 binding site on the nm23-H1 promoter and activated its expression Results suggest that the Fas signal favors the Th17-phenotypic features of T cells through the caspase-1/Stat3 signaling pathway. Expression of STAT3 protein in 80 thymic epithelial tumors was detected by immunohistochemistry. Positive expression of STAT3 protein was associated with Masaoka staging and WHO histological classification, but not with age, gender, or tumor size. The IL-6/STAT3 signalling loop and platelet-derived growth factor-BB (PDGF-BB)/PDGF receptor (PDGFR) pathway were important for CM-induced cell migration and invasion. ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but unlike plasmablastic lymphomas do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression. STAT3 works with HIF1 to activate HIF1 target genes and to drive HIF1-depedent tumorigenesis under hypoxic conditions, but also has HIF-independent activity in normoxic and hypoxic cells. acetylated STAT3-induced promoter gene methylation accounts for the loss of ARHI expression and cancer cell proliferation. STAT3 phosphorylation was activated more in the GBM-SC lines than serum-derived GB cell lines reciprocal crosstalk between the MAPK pathway and STAT3-mediated signal transduction forms a critical axis successively activated by lipopolysaccharides in bladder epithelial cells. Stat3 downstream gene product chitinase 3-like 1 is elevated in lung cancer STAT3 is activated at two phosphorylation sites: Tyr705 and Ser727, and both phosphorylation sites were phosphorylated in lesional psoriatic skin. Down-regulation of GRIM-19 is associated with STAT3 overexpression in breast carcinomas. Leptin may be one of the proinflammatory cytokines that up-regulates IL-6 production in rheumatoid synovial fibroblasts via activation of JAK2/STAT3. TGF-beta1 up-regulates STAT3 activation and HIF-1alpha stabilization, which leads to TWIST1 expression in a prostate cancer invasion cascade STAT3 signaling and invasion in human melanoma cell lines is regulated by mitogen-activated protein kinase (MAPK) signaling High STAT3 expression is associated with acute myeloid leukemia. An interaction between neuroblastoma cells and their microenvironment is mediatwed by the IL-6-STAT3 pathway. miR-124 expression is significantly reduced in glioblastoma and inhibits STAT3. Among signaling pathways that regulate Mcl-1 gene expression, only constitutive STAT3 phosphorylation was suppressed by chrysin. Stat3 is an independent risk factor for subsequent thrombosis during follow-up. Inhibition of the STAT3 pathway by phosphor-valproic acid inhibits pancreatic cancer growth in mice. Data indicate that metastatic breast cancer (BC) cells that failed to activate STAT3 downstream of EGFR did display robust STAT3 activity upon adhesion to fibronectin (FN). These results suggest that not all patients with Hyper-IgE syndrome who had NIH scores over 40 points carry STAT3 mutations, those whose Th17 cell numbers strikingly decreased probably had autosomal dominant Hyper-IgE syndrome with STAT3 mutations. Taken together, these results suggest that the pharmacological inhibition of STAT3 may be a promising therapeutic strategy for the management of chemoresistance in ovarian cancer. Positive expression rate of IL-6/STAT3 was 39.7% (23/58)/29.3% (17/58) in primary Wilms' tumor tissues, while 61.1% (11/18)/33.3% (6/18) in associated invasive/metastatic tissues. Identification of canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the intracellular domain of the interleukin 23 receptor. IL-22/STAT3 signaling pathway may be related to ulcerative colitis and UC-induced carcinogenesis and IL-22 can be used as a biomarker in judging the severity of UC. AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in esophageal squamous cell carcinoma, as well as in lung and breast cancer. these results define a novel signaling network whereby JAK2/STAT3 signaling creates a feed-forward loop to raise activated WASF3 levels that promote cancer cell motility. STAT3 binds indirectly in complexes with NF-kappaB to the GADD45G promoter. Variant G6PD levels promote tumor cell proliferation or apoptosis via the STAT3/5 pathway in the human melanoma xenograft mouse model. STAT3 plays a role in the life cycle of HCV and have clarified the role of STAT3 as a proviral host factor. Results suggest that LPLUNC1 can inhibit inflammation and nasopharyngeal carcinoma (NPC) growth by downregulating the Stat3 pathway. STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation. The presence of activated STAT3 has a profound effect on miR expression in CLL cells. Findings indicate a role of B cells in promoting tumor progression through angiogenesis and identify STAT3 in B cells as potential therapeutic target for anti-angiogenesis therapy. the expression of Oct-4, Nanog, Sox-2 and Stat-3 are related to differentiation in ameloblasts and odontoblasts. Kaposin B significantly contributes to the chronic inflammatory environment by unique activation of the proto-oncogene STAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28. these data indicate a direct role for TEL-AML1, via increasing the activity of RAC1, in regulating the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which results in transcriptional induction of MYC. STAT3 activates miR-155 in chronic lymphocytic leukemia cell strong STAT3 expression in surgical specimens was correlated with an increase in median colorectal cancer overall survival by about 30 months Single nucleotide polymorphisms in STAT3 is associated with non-Hodgkin lymphoma. We therefore conclude that germacrone induces apoptosis through the JAK2/STAT3 signalling pathway. Data suggest that flavanoids (naringenin, flavone) suppress STAT3 signaling and induce expression of SOCS3 (suppressor of cytokine signaling 3) in cultured vascular endothelial cells; thus, dietary components can act as anti-inflammatory agents. results suggest that (i) STAT3 is required for the maintenance of the latent state and interference with its functions leads to reactivation and (ii) p300/CBP is essential for HSV reactivation Our results revealed a novel role of Epstein-Barr virus encoded small non-cdoing RNAs (EBERs) in the coordination of IL-6-STAT3 signaling pathway to chemoresistance and cellular migration in cancer cells. mutation results in impaired host defense against Candida and staphylococci in hyper-IgE syndrome patients Stat3 inactivation and Skp2 degradation regulate cell death pathways in tumor cell lines treated with salinomycin. Higher expression of p-p38, p-C-JUN, p-STAT3, and p-gp130 in the MBC-B group. High STAT5 expression is associated with pancreatic cancer. The STAT3-induced miR-92a promotes cancer invasion by suppressing RECK. Activation of the EGFR/STAT3 signaling pathway may contribute to lymph node metastasis, which can promote the progression of gastric cancer. Data indicate that SOCS-3, STAT-3, and the status of extragastric nodal metastasis were identified to be the independent factors of the lymph node metastasis from gastric cancer (GC). The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. In tumor cells, STAT-3 knockdown inhibited VEGF but not HIF-1alpha expression. HIF-1alpha overexpression increased STAT-3 expression and this was inhibited by ganetespib The miR-1234 expression level correlated inversely with the expression of STAT3. The Stat3 protein was down-regulated in cells transfected with miR-1234, suggesting that STAT3 might be a potential target for miR-1234. Emodin mediated its effects predominantly through inhibition of the STAT3 signalling cascade and thus has a particular potential for the treatment of cancers expressing constitutively activated STAT3. miR-124 was down-regulated specifically in colon tissues from pediatric patients with ulcerative colitis and directly targeted STAT3 messenger RNA inhibition of IGF-IR and targeting of the JAK2/STAT3 signaling pathway can be a target for ovarian cancer therapy. A novel missense (M206K) STAT3 mutation in diffuse large B cell lymphoma deregulates STAT3 signaling. STAT3 plays a regulatory role in HPV16-mediated cervical carcinogenesis. The combination of antrocin and JAK2/STAT3 gene silencing significantly increased apoptosis in H441 cells. These findings uncover a novel mechanism of erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human lung cancer Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The constitutive activation of STAT3 and NF-kappaB signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma. IL-18 induces profibrotic cellular changes and collagen production in renal tubular epithelial cells via STAT3 activation. The signaling cross point of the mitochondrial pathway and the JAK2/STAT3 signaling pathway in C6 glioma cell death is modulated by quercetin-nanoliposomes. expression level of nuclear JAB1, but not nuclear STAT3, correlated with unphosphorylated STAT3 DNA-binding activity between COLO205 and LoVo cells STAT3 knockdown reduces cell proliferation. zinc transporter ZIP6 is transcriptionally induced by STAT3 and unprecedented among zinc transporters, and is activated by N-terminal cleavage which triggers ZIP6 plasma membrane location and zinc influx. Data indicate that the anti-tumor effects of guggulsterone (GS) possibly involve multiple networks including inhibition of FAK, Src, and Jak/STAT signaling. The acquisition of B cell stimulating properties by naive cord blood CD4 T cells required the STAT3-dependent expression of ICOS and IL-21. STAT3-mutant Large granular lymphocyte leukemia clones may be responsible for the primary induction of bone marrow failure in a subset of aplastic anemia and myelodysplastic syndromes patients STAT3 activation promotes oncolytic HSV1 replication in glioma. Data indicate that ruxolitinib effectively inhibited JAK/STAT signalling in hepatocellular carcinoma (HCC) cells with a significant reduction in the expression of JAK downstream targets pSTAT1 and pSTAT3. Data suggest that in prostate cancer cells CDK5 (cyclin-dependent kinase 5) regulates interaction of STAT3 with AR (androgen receptor) through phosphorylation of Ser727-STAT3 and thereby up-regulates AR protein stability. Stat signaling and VEGF expression are inhibited by the antiangiogenic plant flavone acacetin Data indicate that IL-6- and IFN-alpha-induced STAT3 phosphorylation and IFN-alpha-induced STAT1 phosphorylation were impaired in plasmacytoid dendritic cells (pDCs) from Crohn's disease (CD) patients. Data indicate a mechanism that fibroblast senescence promotes cervical cancer development through high-risk HPV16 and HPV18 E6-activated IL-6/STAT3 signalling in tumour microenvironment. Findings indicate the important role of Stat3 in cisplatin resistance in ovarian cancer. These findings place STAT3 at a critical crossroads between Epstein-Barr virus latency and lytic activation, processes fundamental to Epstein-Barr virus lymphomagenesis. Activated STAT3 binds to the MMP3 promoter region and regulates MMP3 in Heme-induced endothelial cell apoptosis. suppression of STAT3 during brain inflammation would inhibit astrogliogenesis and promote neurogenesis. STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive anaplastic large cell lymphoma. Molecular mechanism dissection revealed that targeting prostate cancer cell AR with siRNA promoted cell migration/invasion via CCL2-dependent STAT3 activation and epithelial-mesenchymal transition pathways. Probucol could attenuate tert-butyl hydroperoxide induced mesangial cell senescence by regulating JAK2/STAT pathway. RNA Pol II on HIF1 or HIF2 target genes is primarily associated with HIF1alpha or HIF2alpha in a STAT3 or USF2 dependent manner results demonstrate the role of IL-6-STAT3 signaling in ACS through increased Th17 cell differentiation Stat3 activation in lymphoma cells was involved in this cell-cell interaction. Interleukin-6 up-regulates miR-21 levels via activating STAT3 in HBE cells exposed to arsenite. the role of pSTAT3 in temporal bone squamous cell carcinoma warrants further investigation because there is increasing evidence in preclinical models that inhibiting STAT3 phosphorylation can be a useful addition to different anticancer strategies. The total CTGF production induced by TGF-beta in activated HSCs is therefore, to a large extent, dependent on the balance and integration of the canonical Smad3 and Stat3 signaling pathways Analysis of the STAT3 interactome using in-situ biotinylation and SILAC. STAT3 is an important downstream mediator of the pro-carcinogenic effects of PRKCZ in pancreatic cancer cells. Knockdown of STAT3 causes a significant reduction in tumor burden and delays tumor progression with increased response to gemcitabine. Our data suggest that epithelial STAT3 plays a critical role in inflammation-induced tumor progression through regulation of leukocytic recruitment especially the infiltration of Treg cells in the large intestine. The STAT3 completely abrogated the anti-apoptotic effect and expression of caspase3 in decidual gammadelta T cells induced by human TSLP. Data indicate that supraglottic laryngeal tumor cell lysates (SLTCL) mediated macrophage polarization is STAT3 dependent. results suggest a two-step mechanism, whereby LfcinB induces TIMP-1 through an IL-11-dependent pathway involving transcription factor AP-1 and STAT3. Gankyrin is crucial for cholangiocarcinoma carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein. targeted by miR-130b, which was further confirmed by the inverse expression of miR-130b and STAT3 in pancreatic cancer samples. RKIP and STAT3 have an additive effect on the survival of high-grade glioma. Expansion of myeloid-derived suppressor cells (MDSCs) by mesenchymal stromal cells (MSC)-secreted HGF involves c-Met (its receptor) and downstream phosphorylation of STAT3, a key factor in MDSC expansion. Data suggest HLA-G antigen regulates invasiveness of choriocarcinoma cells and invasiveness of trophoblasts at blastocyst implantation; down-regulation of HLA-G dampens STAT3 activation; up-regulation of HLA-G promotes STAT3 activation/invasiveness. Studied the cytotoxic effect of NO donors on ovarian cancer cell lines, as well as their effect on posttranslational modification of STAT3 and AKT proteins in these cells. SIRT1-specific short-interfering RNA was used to investigate the role of SIRT1 in STAT3 signaling our research data indicate that the anticancer function of green tea results from the inhibition of the STAT3 signaling pathway by EGCG. HIC1 interacts with and modulates the transcriptional activity of STAT3. association between STAT3 SNPs and autoimmune thyroid disease was found in chinese patients. Newly synthesized IL-6 drives association of the IL-6 receptor and gp130 with EGFR, leading to EGFR-dependent rephosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. STAT-3 activation is critical for human plasma cells throughout their maturation. Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression. Data indicate that the IL-32beta-VEGF-STAT3 pathway affects the migration of MDA-MB-231 cells. Human metapneumovirus infection inhibits the phosphorylation and nuclear translocation of STAT3. Increased IL-6-induced activation of STAT3 was observed in neoplastic gastric tissue, which positively correlated with tumor progression. determined whether activation and expression levels of EGFR1, ERK, AKT, STAT3, and TWIST1 are dependent on activating mutations of EGFR1 in NSCLC Ursolic acid inhibits persistently activated STAT3 in cancer stem cells, indicating that STAT3 is a new target for colon cancer prevention. Confluence of cultured lung cancer cells dramatically increases STAT3 activation independent of SRC action. these findings provide new evidence for a positive feedback loop between STAT3 signaling and COX-2 in H. pylori pathogenesis Cross-talk between KLF4 and STAT3 regulates axon regeneration. We identified HAb18G/CD147 as a novel upstream activator of STAT3, which interacts with CD44s and plays a critical role in the development of pancreatic cancer. Review of the contribution of STAT3 to lung cancer growth and progression. [Review] EGF, EGFRvIII, STAT3 and STAT5 have roles in progression of glioblastoma Porphyromonas gingivalis modulates Pseudomonas aeruginosa-induced apoptosis of respiratory epithelial cells through the STAT3 signaling pathway. STAT3 is overexpressed and overactive diffuse large B-cell lymphoma and STAT3 binding associates with oncogenic pathways. results of the activation and varying localisation of STAT3 and its phosphorylated form in nasal polyps suggest that pSTAT3 plays a crucial role in the proliferative development of nasal polyps KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3 in acute kidney injury. Data indicate that IL-21 induces IL-2RA (CD25) in normal, but not STAT3-deficient, naive B cells. investigation of STAT3 tyrosine-705 phosphorylation and its correlation with its possible regulator HER2 in the prognosis of pancreatic ductal carcinoma findings simultaneously reveal how EBV manipulates host STAT3 even before expression of viral oncogenes to facilitate cell survival and proliferation, processes fundamental to EBV lymphomagenesis An opposing role of AR and STAT3 in prostate Cancer stem-like cell development. This study has confirmed that adrenocortical carcinoma overexpress signal transducer and activator of transcription 3 and insulin-like growth factor 2 mutation is associated with diminishes rates of food allergies and anaphylaxis in patients with autosomal-dominant hyper-IgE syndrome Thus, our results suggest a previously unknown Stat3-PTPN13 molecular network controlling squamous cell lung carcinoma development Dominant-negative activity of the STAT3-Y705F mutant depends on the N-terminal domain that miRNAs represent a newly discovered class of regulatory molecules, investigating their biological functions and contribution to pathologies caused by STAT3 dysregulation is essential to improve our understanding of tumorigenesis In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling. these findings show that miR-124 functions as tumor suppressor in hepatocellular carcinoma (HCC) by targeting STAT3, and miR-124 may therefore serve as a biomarker for diagnosis and therapeutics in HCC. In contrast to naive B cells, STAT3-deficient memory B cells responded to STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. The Multiple myeloma samples seemed to show elevated basal level of Stat3 phosphorylation. TNF-alpha-induced activation of NF-kappaB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Scoparone might bind the SH2 domain of STAT3. STAT3 activity regulates the cycling of quiescent dental pulp stem cells to determine their fate. Authors have discovered a STAT3-dependent Akt activation that impairs the efficacy of gefitinib. Results demonstrate the remarkable correlation of STAT3 mutation with PRCA, neutropenia and ss2-MG. Restored STAT3 expression through treatment with IL-6 cytokine partly abolished miR-124-mediated cell cycle arrest and apoptosis induction. IL-21 signals through the STAT-3 and STAT- 5b signaling pathway in the CIK cell pool. The autocrine IL-6 pathway induces enzalutamide resistance in prostate cancer cells via the constitutive activation of Stat3. study shows that the MEK-ERK pathway is required for activated Ras-induced phosphorylation of STAT3 on S727, that inhibition of STAT3 S727 phosphorylation contributes to the anti-oncogenic potential of MEK inhibitors CD24 mediates gastric carcinogenesis and may promote GC progression by suppressing apoptosis and promoting invasion, with the activation of STAT3 playing a critical role. Targeted blockade of the STAT3 signaling pathway with a decoy oligodeoxynucleotide may represent a potential therapeutic approach in the treatment of ovarian cancer. High STAT3 or phospho-STAT3 expression is a strong predictor of poor prognosis among patients with NSCLC. STAT3 protein expression is a strong indicator of poor prognosis and survival of patients diagnosed with non-small-cell lung cancer. phospho-STAT3(review) Data indicate that CTLA4Fc fusion protein activates STAT3, which is critical for dendritic cells (DCs) function. A panel of miRNAs is regulated through promoter binding of the STAT3 in human macrophage and these miRNAs are involved in anti-apoptosis in response to T. gondii infection. Hes1-mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human intestinal epithelial cells. The secretome of senescent melanoma cells activates the STAT3 pathway and STAT3 inhibition prevents secretome effects, including the acquisition of tumorigenic properties. The SH2 domain of the STAT3 gene is frequently mutated in Asian T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorders of natural killer cells. These findings uncover a novel mechanism of radioresistance and provide a more effective approach to overcome radioresistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway. The level of p-Stat3 was found to be higher in imatinib therapy resistant cases of chronic myeloid leukemia than in responsive cases, which suggest the beneficial use of p-Stat3 as an indicator to follow the clinical course and the treatment response. These studies demonstrate an important role for STAT3 signaling in ALDH(+) and ALDH(+)/CD44(+)/CD24(-) subpopulations of breast cancer cells. The EGFRvIII-STAT3 pathway promotes cell migration and invasion by upregulating S100A11 in hepatocellular carcinoma. It has been shown that rs3816769 STAT3 gene polymorphisms are associated with Nonsmall cell lung cancer susceptibility and might be regarded as having a significant functional and diagnostic value. activation of STAT3 signaling leads to regulation of hTERT pathway STAT3 may affect astrocytoma invasion, expression of pSTAT3(Tyr705) is a significant prognostic factor in tumor recurrence and overall survival in astrocytoma patients. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade. HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis. (E)-2,4-Bis(p-hydroxyphenyl)-2-butenal enhanced TRAIL-induced ovarian cancer cell apoptosis via NF-kappaB/STAT3 signaling. Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways tumor-specific mutational events in the PTPRT gene can serve as direct drivers for tumor growth by inducing hyperactivation of STAT3, a potent oncogenic transcription factor and PTPRT substrate in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-kappaB and STAT3 pathways for lung cancers harboring mutant EGFR vOur study clearly demonstrates that the predominant effect of this combination is the reduction of signaling molecules including STAT3, STAT5b, IGF-1R, VEGF and VEGF-R2 which are involved in the growth, progression and metastasis of human bladder cancer these data demonstrate that XPO1 inhibition by SINE compounds represses STAT3 transactivation to block the selective oncogenic properties of survivin and supports their clinical use in triple-negative breast cancer . We demonstrate a mechanism by which EGF promotes prostate cancer cell progression through a ROS/STAT3/HIF-1alpha/TWIST1/N-cadherin signaling cascade, providing novel biomarkers and promising therapeutic targets for prostate cancer cell progression. NF-kappaB and STAT3 signaling pathways, as main inflammatory mediators, are found to be activated in urothelial bladder carcinoma. We propose that the natural compound 2-MS, as a potent dual inhibitor of STAT3 and NF-kappaB pathways, is a promising anticancer drug candidate. our results suggest a previously unknown Stat3-LGR4 molecular network, which may control osteosarcoma development and progression genetic association studies in Croatian population: Data suggest that an SNP in STAT3 (rs744166) is not associated with susceptibility to or severity of Hashimoto's thyroiditis in the population studied. [PILOT STUDY] Core is capable of up-regulating NANOG expression Blockage of Stat3 with a selective inhibitor, S3I-201, or siRNA presents an effective strategy to overcome resistance to PI3K/Akt/mTOR inhibition in non small-cell lung cancer cells. data support the existence of a signaling cascade by which stimulation of macrophages with the IL-10 cytokine determines a sequential activation of STAT3 and MafB transcription factors higher expression of miR-146b was positively correlated with patient survival in breast cancer subtypes with increased IL6 expression and STAT3 phosphorylation. Signal transducers and activators of transcription 3 suppression by JMJD2B silencing enhanced DNA damage. Loss of SOCS3 increased tumor growth, migration, and invasion and resulted in accompanied changes in expression of STAT3 and its target oncoproteins. Association of MCL-1 with STAT3 modulates the normal, anti-apoptotic, activity of MCL-1, resulting in pro-apoptotic effects. Inhibition of the STAT3 gene decreases HeLa cell migration, moreover the blocked STAT3 ability to the antyapoptotic gene expression activation leads to the increased susceptibility to apoptotic cell death. study thus identified a mechanism by which STAT3 signaling can be inhibited in pancreatic cancer cells by modifying let-7 expression This mitoStat3-mtDNA interaction may represent an alternate signaling pathway that could alter mitochondrial function and biogenesis and have a role in tumorigenesis. Data show that T-cell transcription factor GATA-binding protein 3 (GATA-3) expression identifies a subset of T-cell lymphomas PTCL, NOS with a distinct cytokine profile and inferior survival. These findings may provide a novel linkage between the EGFR and STAT3 signaling pathways and the activation of cyclin D1 by LMP1 in the carcinogenesis of NPC. Our data indicate the presence and involvement of Stat3/STAT3-dependent Treg17 cells that specifically target Th17 cells in murine and human crescentic glomerulonephritis. activating mutations specific for large granular lymphocytic leukemia [review] STAT3 and NFkappaB synergistically act for maximum induction of FAT10 expression. downregulation of STAT3 or Survivin can suppress the proliferation of T24 bladder cancer cells. RhoC has a role in regulating cancer stem cells in head and neck squamous cell carcinoma through the over expression of IL-6 and phosphorylation of STAT3 Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-beta (TGF-beta) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. STAT3 bound to previously undescribed negative regulatory elements within the promoter of PRKCB, which encodes PKCbetaII. NOX1 is involved in acure respiratory distress syndrome pathophysiology and is responsible for the damage occurring in alveolar epithelial cells at least in part via STAT3 signalling pathways. IL-6/JAK/STAT3 signaling pathway is active and may play an important role in the mechanisms of epithelial hyper-proliferation responsible for cholesteatoma. findings reveal unique structural characteristics of STAT3 within the STAT family and contribute to the understanding of the L78R mutation found in inflammatory hepatocellular adenoma Inactivation of Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of esophageal squamous cell carcinoma by facilitating crosstalk between apoptosis and autophagy. In conclusion, here we show that STAT3 activation can be one of the molecular mechanisms leading to KSHV-mediated DC dysfunction, that might allow viral persistence and the onset of KSHV-associated malignancies. Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis. The promoter of the miR-17-92 gene cluster is transactivated through the promoter binding of STAT3 while BIM expression is decreasesed during Toxoplasma gondii infection. Cell survival under unstressed conditions is due to cell type-specific autophagy regulation of STAT3 activity. overexpression of hsa-miR-4516 downregulates STAT3, p-STAT3, CDK6, and UBE2N proteins that are consistently upregulated in psoriasis and induces apoptosis in HaCaT cells. A functionally distinct, noncanonical STAT3 phosphoform positively regulates target gene expression in a combinatorial signaling context. Studied a new therapeutic alternative in the treatment of multiresistant lung adenocarcinoma via siRNA-specific transfection of six crucial molecules involved in lung carcinogenesis: SFR, E2F1, Survivin, HIF1, HIF2 and STAT3. Data indicate that proteasomal subunit X PSMB5 is a target of signal transducer and activator of transcription 3 (STAT3). STAT3 interrupts ATR-to-Chk1 signaling by promoting loss of Claspin, a protein that assists ATR to phosphorylate Chk1. IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. Phosphorylated STAT3 and PD-1 regulate IL-17 production and IL-23 receptor expression in Mycobacterium tuberculosis infection. STAT3 Tyr705 phosphorylation may have a role in clinical outcome in patients with newly diagnosed supratentorial glioblastoma data suggest that the pancreatic cancer tumor microenvironment transforms monocytes to monocytic myeloid-derived suppressor cells by STAT3 activation our results suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo NSCLC cells could be sensitized to cisplatin by targeting STAT3 with chemically modified siRNAs together, a fact which was accompanied with increased apoptosis. Data indicate that signal transducer and activator of transcription 3 (STAT3) silenced monocyte-derived dendritic cells promoted a higher interferon gamma production by CD4(+) naive T cells. Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 promotes cell proliferation and migration by upregulating DNMT1 via STAT3 activation. downregulation of LKB1 expression suppresses Stat3 activity that may promote tumor growth during esophageal cancer progression. the present study found that STAT3 (-/p) expression was positively correlated with miR-21 in 60 oral squamous cell carcinoma samples. STAT3 activity is increased in macrophages following mTOR induction, thus contributing to development of atherosclerosis. elevated STAT3 activity in lymph nodes prior to tumor cell arrival may indicate a poorer prognosis in gastric cancer IL-17 influences the innate immune system in rheumatoid arthritis by increasing the synovial expression of TLR3 via the STAT3 pathway. OSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. ERK1/2 as well as STAT3 (Ser727) phosphorylation play an important role in LIF-mediated JEG-3 trophoblastic cell invasion and gene expression Compared to wild-type STAT3, the STAT3 R414K/R417K mutant shows attenuated tyrosine phosphorylation and it is a less active transcription factor. Stat3 activity is regulated by CK2 at its phosphorylation Ser-727 residue. Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. High STAT3 expression is associated with non-small-cell lung cancer. IFN-alpha, a member of the type I IFN family, differentially modulates TLR7/8- and TLR9-activated STAT3 and ERK in B cells, which provides an explanation for our findings that IFN-alpha enhances TLR7/8-induced, but not TLR9-induced IL-10 production analysis showed binding of STAT3 to AHSP promoter and binding was significantly augmented with IL6 stimulation and upon alpha-globin overexpression work identifies STAT3 binding long noncoding RNA lnc-DC (LOC645683) that regulates dendritic cell (DC)differentiation; lnc-DC bound directly to STAT3 in the cytoplasm, which promoted STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding t [...] Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. our results suggest that the activated Stat3 may represent an important mechanism for Beclin 1 downregulation in nonsmall cell lung cancer development Endothelial cells from aging individuals have impaired angiogenesis and reduced expression of VEGF likely due to impaired nuclear transport of P-STAT3 and P-CREB transcription factors in these cells. Our study implies that the STAT3 rs2293152 polymorphism may be associated with the occurrence of UC and might be used as a predictive factor for UC in the Chinese Han population. NPM is a downstream effector of the STAT3 signaling, and can facilitate the nuclear entry of phosphorylated STAT3. Zerumbone is a novel blocker of STAT3 signaling. Study provides new insight into the regulation of Epithelial-mesenchymal transition by IL-6 via activation of Stat3 in human cervical carcinoma. High STAT3 expression is associated with neuroblastoma. IL-22 Promotes Colon Cancer Stemness via STAT3 Activation Mahanine suppresses STAT3 activation and promotes ubiquitin-dependent proteasomal degradation of p-STAT3. HPV-16 E2 may regulate NF-kappaB and STAT3 activation in the presence of TNF-alpha with implications on the survival of HPV-infected cells. the E3 ubiquitin ligase seven-in-absentia-2 (SIAH2) accelerates the proteasomal degradation of TYK which consequently suppresses the activation of STAT3 in non-small-cell lung cancer activation of STAT3 induces the expression of GM-CSFRalpha that protects CLL cells from apoptosis, suggesting that inhibition of STAT3 or GM-CSFRalpha may benefit patients with chronic lymphocytic leukemia We reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16(INK4A) deletion, as a driver of glioma progression. UDP-glucose activates P2Y14 receptor and JAK2, increases STAT3 Tyr705 phosphorylation, and enhances transcription of HAS2. The STAT3 pathway is enhanced during stroke development by IL-32alpha. HPV 16 infection induce upregulation of HER2/neu, pStat3 and IFI16. polymorphisms in STAT3, along with environmental factors, might be associated with the development of gastric cancer. Data indicate that STAT3 transcription factoris a potential target of miR-520a-5p. IL-10 apparently inhibits fibrosis by activating AKT and STAT3 phosphorylation downstream of the IL-10 receptor Microvessel morphometry was unrelated to proangiogenic cytokines, p-STAT-3, SOCS-3, or survival STAT3 rs744166 and rs4796793 polymorphisms may be associated with Crohn's disease occurrence and used as a predictive factor of CD in Chinese Han populations. Inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the 'stemness' profile in chemotherapy-treated residual ovarian tumor cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These results support STAT3 signaling activity as another functional marker for human breast cancer stem cells. binding of STAT3 to a predicted STAT3 binding site upstream of the NKG2D gene is enhanced by IL-10 and IL-21 CTLA4 expression is observed in T cells of patients with blood malignancies, and CTLA4(apt)-STAT3 siRNA treatment of immunodeficient mice bearing human T cell lymphomas promoted tumor cell apoptosis and tumor growth inhibition. Atopic dermatitis patients showed significantly higher nTreg-cell counts compared to STAT3-hyper-IgE syndromes and control individuals For all the three STAT3 constructs. LKB1 is differentially regulated by PRL at the level of transcription in representative human breast cancer cells. Its promoter is targeted by STAT3 and STAT5A, and the cellular estrogen receptor status may affect PRL-responsiveness Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain. RECK controls this angiogenic rheostat through a novel complex with cell surface receptors to regulate STAT3 activation Data demonstrate that the serum levels of SOCS3 and STAT3 were increased in childhood atopic dermatitis (AD) compared with controls. miR-221 and miR-222 act in a positive feedback loop to increase expression levels of RelA and STAT3 in colorectal neoplasms. Antagonism of miR-221 and miR-222 reduces growth of colon tumors in mice with colitis. Among all women, there was a positive correlation between JAK2 and STAT3 expression Data indicate that fucoidan induces apoptosis through the down-regulation of signal transducer and activator of transcription 3 (p-Stat3). data presented herein confirmed the occurrence of a redox-dependent regulation of STAT3, identified the more redox-sensitive cysteines within STAT3 structure, and may have important implications for development of new drugs FGF2 is required for motor neuron differentiation from human neural stem cells and that inhibition of STAT3 further increases motor neuron differentiation at the expense of astrogliogenesis. The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. AURKA regulates JAK2-STAT3 activity in human gastric and esophageal cancers 6SG also suppressed the expression of STAT3-regulated gene products. STAT3 pathway plays an important role in mediating tumor-initiating capacities in nasopharyngeal carcinoma and suggest that inactivation of STAT3 with EGCG may represent a potential preventive and therapeutic approach. Data indicate that ubiquitin specific peptidase 22 (USP22)-mediated sirtuin 1 (SIRT1) deubiquitination inhibits STAT3 transcription factor acetylation and its transcriptional activation. Activation of STAT3 protein leads to uncontrolled cell proliferation. STAT3 provides a negative-feedback safety mechanism that limits tissue damage by T helper (Th)17 cells during chronic inflammation, demonstrating that active STAT3 in high density cultures may enhance the formation of IL-17-producing memory T cells. Suppression STAT3 signaling is implicated in kurarinol-mediated hepatocellular cell apoptosis. HIV-1 gp120 activates the STAT3/interleukin-6 axis in primary human monocyte-derived dendritic cells. Common variations of STAT3 could significantly affect the risk of obesity and hypertriglyceridemia in Chinese Han population. the high proportion of pSer727-STAT3 positive neoplastic cells in glioblastoma is an independent unfavorable prognostic factor Our data indicate that expression of both CD44s and pSTAT3 in clear cell renal cell carcinoma is associated with advanced tumor stage and patient survival data thus provide important and novel insights into the roles of MRTF-A and STAT3 in regulating MDA-MB-231 cell migration. The critical role of STAT3 in autoimmune disease. Pretreatment with a STAT3 inhibitor also augmented SRP induced growth inhibition and cell apoptosis. Investigated the effects of mTOR-STAT3 pathway on the invasion and migration of hepatoma cells. IL-22 conferred resistance to 5-FU and OXA by inducing IL-8 autocrine expression through STAT3 activation. RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs Many drug-treated oncogene-addicted cancer cells engage a positive feedback loop leading to Stat3 activation. MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the Epithelial-mesenchymal transition of breast cancer stem cells by down regulating the STAT3 pathway ISL-1 is tightly linked to non-Hodgkin lymphoma proliferation and development by promoting c-Myc transcription, and its aberrant expression was regulated by p-STAT3/p-c-Jun/ISL-1 complex activation. Suggest tectochrysin leads to apoptotic cell death in NSCLC cells through activation of DR3 and Fas expression via inhibition of STAT3 phosphorylation. Data support a model in which EWS/FLI1 deficiency results in the secretion of soluble factors, such as IL6, which activate STAT3 in bystander cells that maintain EWS/FLI1 expression. in human HCC tissues, SPTBN1 expression correlated negatively with expression levels of STAT3, ATF3, and CREB2; SMAD3 expression correlated negatively with STAT3 expression TLR9 ligands induce S100A8 in macrophages via a STAT3-dependent pathway which requires IL-10 and PGE2. STAT3 is negatively regulated by lupeol, inhibiting growth and inducing apoptosis, in hepatocellular carcinoma cells. STAT3 signaling in human cancer cells is blocked by N6-substituted adenosine analogues, a novel class of JAK2 inhibitors STAT3 and MMP-2 have a role in the diagnosis of colon adenocarcinoma and the detection of the degree of differentiation Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival. This study directly depicts STAT3-mediated miRNA profiles in CRC cells, which provides a possible way to discover biomarkers for Colorectal cancer therapy. ATF4 may promote multidrug resistance in esophageal squamous cell carcinoma cells through the up-regulation of STAT3 expression These data suggest that the STAT3 locus is associated with both inflammatory bowel disease and colon cancer STAT3 is a critical signaling node in BCR-ABL1 tyrosine kinase-independent leukemia resistance that is reversed by a discovered BP-5-087. Gain-of-function and loss-of-function studies with cultured mouse and human basal cells suggest that IL-6/Stat3 signaling promotes ciliogenesis at multiple levels. STAT3 binds to the -201 to -210 region of PRL-3. STAT3 functionally regulates PRL-3. STAT3 core signature was enriched in AML with high PRL-3 expression. The STAT3/PRL-3 regulatory loop contributes to the pathogenesis of AML. These findings demonstrate a distinct role for STAT3 signaling in basal breast cancers, and underscore the importance of considering subtype-specific molecular pathways that contribute to tissue-specific cancers. AngII/Rac1/STAT3 signaling as a mechanism for atrial structural remodeling the inhibition of STAT3 signaling by NDRG2 suppresses EMT progression of EMT via the down-regulation of Snail expression Factors released by CBMSCs protect endothelial cells from the deleterious impact of GSD by activation of the STAT3 survival pathway These results illustrate the novel activity of the C5a-C5aR axis that promotes human NPC cell proliferation through PCAFmediated STAT3 acetylation. IL-10/Janus kinase/STAT3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome. Expression of p-STAT3 is upregulated in peripheral CD4+ and CD8+ T cells of hepatocellular carcinoma patients. Incubation of hepatocarcinoma cell lines with tocilizumab or knockdown of signal transducer and activator of transcription 3 reduced the ability of macrophages to promote sphere formation by CD44+ cells. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. TRPM7 activates JAK2/STAT3 and/or Notch signaling pathways and leads to increased cell proliferation and migration. The present study concluded that IL-27 reduces lipid accumulation of foam cell by upregulating ABCA1 expression via JAK2/STAT3. results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus NTS/IL-8/CXCR1/STAT3 signaling is crucial for the maintenance of stem-like traits in glioblastoma stem cells . Data suggest that STAT5A and STAT5B (highly conserved genes; 96% identity in amino acid sequences) are nearly identical in responses to growth hormone; STAT1 and STAT3 exhibit weaker binding to DNA elements in insulin-like growth factor-I gene. IL-22 activates miR-197 expression through the binding of phosphorylated STAT3 to sequences in the putative promoter of miR-197. By inducing autophagy via the ERK/AKT-mTOR-STAT3-Notch signaling cascade. In addition to IL-6, TNF-alpha increases Stat3 and NFkappaB binding to the fascin promoter to induce its expression. Unphosphorylated-STAT3 plays an important role in angiotensin II-induced gene expression and in the consequent development of cardiac hypertrophy and dysfunction. The present study provides compelling experimental evidence that Ang-II/AT1 receptor/STAT3 is an important signaling pathway in the atrial myocardium. The data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. ER stress induced endogenous expression of CCL5 via elevating U-STAT3 expression; however, ER stress inhibited CCL5 secretion, which in turn, decreased the transmigration of breast cancer MCF-7 cells. IL-6 has a major role in activating breast stromal fibroblasts through STAT3-dependent AUF1 induction Results suggest that piperine may exert at least part of its anti-cancer effect by controlling interleukin-6 (IL-6) expression through the suppression of p38 MAPK and STAT3 protein. A novel IL-6/Stat3-miR-17-92 cluster-PTEN signaling axis is crucial for cholangiocarcinogenesis and tumor progression. To be associated with signal transducer and activator of transcription 3 pathway inhibition. High Stat3 protein expression is associated with lung cancer. Oncostatin M and leukaemia inhibitory factor trigger signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 pathways but result in heterogeneous cellular responses in trophoblast cells. STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM-induced cellular scattering. Data suggests that targeting both tumor initiating and differentiated cell populations by STAT3 inhibition is predicted to have greater efficacy for prostate cancer treatment. NDRG2/gp130/STAT3 pathway can mediate the antimetastatic effects of Dp44mT in hepatocellular carcinoma. ZER suppressed EGF-induced CD44 expression through inhibition of the STAT3 pathway. Therefore, we suggested that ZER may act as a promising therapeutic drug for the treatment of breast cancer. STAT3 activation in T-cells with neoplastic morphology is associated with the presence of eosinophils in situ and that malignant T-cell lines produce activators of eosinophils through both STAT3-dependent and -independent pathways. IL-32theta;, through its interaction with PKCdelta, downregulates CCL5 expression by mediating the phosphorylation of STAT3 on Ser727 to render it transcriptionally inactive. STAT3 mutations are associated with large granular lymphocytic leukemia progression. results demonstrated that feedback activation of the IL6-STAT3 loop lead to acquired resistance to PI3K inhibitors by promoting EMT and CSC-like features associations between STAT3 rs744166 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease Mitochondrial pSTAT3Ser(727) is part of the antioxidant defense pathway of chronic lymphoid leukemia B cells that regulates their viability. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer. RRAD promotes EGFR-mediated STAT3 activation and induces temozolomide resistance of malignant glioblastoma. CCL2 greatly enhanced IL-6-induced EMT events mainly by upregulating the expression of Twist. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-centered loop and markedly suppressed Twist expression as well as IL-6/CCL2-mediated EMT induction On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. LIF has a role in negatively regulating tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers Suggest that feedback activation of STAT3 via up-regulation of MUC1/4 expression constitutes a key node mediating trastuzumab resistance. CYP2E1 expression regulation occurred via a transcriptional mechanism involving STAT3. Data suggest that RKIP inhibits gastric cancer metastasis via the downregulation of its downstream target genes STAT3 and cyclin D1. pSTAT3-VEGF signaling pathway, which is correlated with peritumoral edema extent, might be a regulatory mechanism in the course of peritumoral edema formation during glioblastoma tumorigenesis and progression. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. [review] Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. The STAT3/beta-catenin interaction is complex but may reduce the proliferative activity of beta-catenin possibly by taking beta-catenin protein beyond the optimal level. results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages These results suggest that calpain plays an important role in E. histolytica-induced degradation of NF-kappaB and STATs in colonic epithelial cells, which ultimately accelerates cell death. STAT3 activation is related to the up-regulation of miR-17-92 clusters in retinoblastoma cells via positive feedback loop between them These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Activation of miR-21 by STAT3 induces proliferation and suppresses apoptosis in nasopharyngeal carcinoma by targeting PTEN gene JAk2/STAT3 plays a key role in CCR7 regulatingSquamous cell carcinoma of the head and neck metastasis. our results show that 20(S)Rg3 inhibits the Warburg effect by targeting STAT3/HK2 pathway in ovarian cancer cells, highlighting the potentiality of 20(S)Rg3 to be used as a therapeutic agent for ovarian cancer these findings revealed that macrophages that have infiltrated tumors may induce epithelial-mesenchymal transition of HCC cells via the IL-8 activated JAK2/STAT3/Snail pathway. Stat3, phosphorylated Stat3, and MMP2 were overexpressed in esophageal squamous cell carcinoma (ESCC) and associated with invasion of ESCC. Stat3 up-regulated expression of MMP2 in ESCC through directly binding to the MMP2 promoter. High STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer. BIS targeting induces cellular senescence through the regulation of 14-3-3 zeta/STAT3/SKP2/p27 in glioblastoma cells. Studied the possible relationship between STATIP1, STAT3 and CML resistance. Data show that cultured keratinocytes treated with STAT3 transcription factor inhibitor (Stattic) survived longer, produced higher titers of virus, and showed reduced activation of type I interferon responses and inflammatory cytokines release. CD147 has a role in promoting Src-dependent activation of Rac1 signaling through STAT3/DOCK8 during the motility of hepatocellular carcinoma cells Cten expression mediates invasion of human lung cancer cells and is upregulated by epidermal growth factor via STAT3. High STAT3 expression was associated with pancreatic cancer. High serum leptin may reduce endometrial receptivity by activating the STAT3 signal pathway and down-regulating gamma-ENaC expression in the endometrium. SOCS3 and STAT3 are the major controllers of the outcome of infection with Mycobacterium tuberculosis. (Review) reveal a novel role for E2 in regulating the activities of NF-kappaB and STAT3 that may have implications in carcinogenic progression of HPV16-infected cells under conditions of stromal inflammation High SMYD3 and pSTAT3 expressions may indicate poor prognosis of patients with gastric cancer These findings suggest that INPP5F is a potential tumor suppressor in gliomas via inhibition of STAT3 pathway, and that deregulation of INPP5F may lead to contribution to gliomagenesis. The results provide evidence that the regulation of IL-6, IL-10, c-Jun, and STAT3 gene expression in Chronic lymphocytic leukemia B cells is clearly different from normal B lymphocytes. Mechanical stretch upregulated fibronectin and TGF-beta1 expression and activated STAT3 in proximal renal tubular epithelial cells. Our findings demonstrate that leptin-induced STAT3 is partially cross activated through SK1-mediated IL6 secretion and gp130 activation. Positive correlations in human tissues suggest the potential significance of this pathway in ER-negative breast cancer Endocytic AMR controls TPO expression through Janus kinase 2 (JAK2) and the acute phase response signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro These results indicated that STAT3 and STAT5b polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis in breast cancer patients. Increased expression of the Th17-IL-6R/pSTAT3/BATF/RorgammaT-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung signalings can reciprocally and positively regulate each other, leading to enhanced non-small cell lung cancer (NSCLC) cell proliferation and survival. this study identified a marked activation of Human beta-defensin-2 expression in human alveolar epithelial type II cells by IL-22 through STAT3-dependent mechanisms. STAT3/miR-21 axis could be a candidate therapeutic target for OSCC chemoresistance. Data indicate that ethanol extract from Sedum sarmentosum (ESB) inhibits HepG2 cell proliferation and induces apoptosis by inhibiting signal transducer and activator of transcription 3 (STAT-3) signaling. our findings suggest that miR-124 functions as a tumor suppressor by targeting STAT3, and that miR-124 may potentially serve as a useful biomarker for the prognosis of non-small cell lung cancer patients. Cigarette smoke-induced MMP2 and MMP9 secretion from aortic vascular smooth cells is mediated via the Jak2 and Stat3 pathway Results demonstrate existence of a functional loop involving Let-7a, STAT3 and miR-21 which were found potentially regulated by viral oncoprotein E6. A novel mutation in the STAT3 in Hyper IgE syndrome is reported Notch1 promotes epithelial-mesenchymal transition and the cancer stem cell phenotype through induction of STAT3. Curcumin and epigallocatechin gallate specifically inhibit STAT3 phosphorylation in cancer stem cells. STAT3 and cyclinD1 correlate with more aggressive tumor behavior in esophageal squamous cell carcinoma. When STAT3 and cyclinD1 are considered together, they serve as effective prognostic markers in patients with surgically resected ESCC. Stat3 was found to directly interact with 14-3-3zeta and its disruption relieved the inhibition induced by 14-3-3zeta in tumor inflammation; study provides evidence that 14-3-3zeta may regulate tumor inflammation and immune response through Stat3 sig [...] Suggest that under conditions of sustained increases in hexosamine biosynthetic pathway activity there is an increase in basal STAT3(Y705) phosphorylation that cannot be further increased by leptin. the present study revealed the aberrant expression of STAT3 and miR21 in hepatocellular carcinoma side population cells. Our data suggested that tumor-associated macrophages might induce drug resistance through IL-10/STAT3/bcl-2 signaling pathway increased activity in the IL-15-derived dendritic cells has a key role in their high effector function STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells MicroRNA-10a silencing reverses cisplatin resistance in the A549/cisplatin human lung cancer cell line via the transforming growth factor-beta/Smad2/STAT3/STAT5 pathway Butein ameliorated colitis in IL-10(-/-) mice by regulating IL-6/STAT3 and MMP-9 activation. MicroRNA-19a functions as an oncogenic microRNA in non-small cell lung cancer by targeting the suppressor of cytokine signaling 1 and mediating STAT3 activation Suggest that ERp57-STAT3 regulation functions in radioresistance of laryngeal cancer. Phosphorylated placental STAT3 is increased in women with polycystic ovary syndrome. STAT3 inhibitor OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. PTPRK underexpression leads to STAT3 activation and contributes to nasal NK/T-cell lymphoma pathogenesis STAT3 overexpression reduced E-cadherin and beta-cadherin. It enhanced N-cadherin and vimentin expression in SMMC7721 cells. STAT3 may bind the Twist promoter, mediate its transcriptional activity, and then promote the EMT in SMMC7721 cells. Taken together, these results illustrate that, as a potent inhibitor of HIF-1alpha and Stat3 signaling, LB-1 exhibits antitumor effect and could be potentially used to treat pancreatic cancer. pSTAT3 Y705 is increased in T4 cells among human recipients of allogeneic HCT before the onset of Grade II-IV acute GVHD. STAT3 signaling and resultant Th17 tissue accumulation are associated with acute GVHD onset, severity, and treatment outcome. High STAT3 expression is associated with the pathogenesis of myeloproliferative neoplasm. fad104 suppressed the invasion and metastasis of melanoma cells by inhibiting activation of the STAT3 signaling pathway Our data demonstrate that the JAK/STAT3 pathway is a common mediator of astrocyte reactivity that is highly conserved between disease states PDLIM2 repression is essential for KSHV-induced persistent activation of nuclear factor kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) and subsequent tumorigenesis and tumor maintenance To drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. The overexpression of B7-H3 induces resistance to apoptosis in colorectal cancer cell lines by upregulating the Jak2-STAT3 signaling pathway SOCS3 negatively regulates proliferation and angiogenesis of NCI-H446 cells and that HIF-1alpha is required in this process. The results also suggested a suppressive role of SOCS3 in Akt signaling, but not STAT3 signaling to block HIF-1alpha expression the expression of IL-6 was significantly higher in MBT-SCs. Additionally, the expression of STAT3 in MCF-7 cells increased slightly when they were co-cultured with malign breast tissue-derived stromal cells revealed a tri-lateral relationship among HPV infection, Stat3 activity and IL17 level, whose collaborative act may orchestrate a proinflammatory microenvironment in the colorectum that may promote carcinogenesis and possibly facilitate progression of CRC Decreased STAT3 in human idiopathic fetal growth restriction contributes to trophoblast dysfunction. STAT3 functions via cellular PCBP2 to regulate B-cell lytic susceptibility by restraining Epstein-Barr Virus lytic activation. Targeted bovine-derived proteins were evaluated for their effects on signal transducer and activator of transcription-3 (STAT3) phosphorylation in human skeletal muscle cells. STAT3 controls NF-kappaB-induced IL-8 expression by sequestering NF-kappaB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. Authors identified nuclear pSTAT3 expression in 59.76 % of tumors. pSTAT3 expression was correlated with differentiation degree of tumors, lymph node metastasis status, clinical stage of tumors and the prognosis of NSCLC patients after resection. Noncanonical STAT3 activation regulates excess TGF-beta1 and collagen I expression in muscle of stricturing Crohn's disease. GP130/STAT3 pathway is activated in NAFLD and can worsen insulin resistance while protecting against other lipotoxic mechanisms of disease pathogenesis. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. aberrant activation of STAT3 signaling plays an important role in the pathogenesis of endometriosis this study proposes the existence of an aberrant IL-6/STAT3/Fra-1 signaling axis leading to colorectal cancer aggressiveness through epithelial-mesenchymal transition induction Decreased Stat3 expression and activation may play an important role in the pathogenesis of preeclampsia. This study collectively showed that Polygonum flavonoids could induce liver carcinoma cell apoptosis both in vitro and in vivo. Efficacy of the FLLL32 pharmacological inhibitor in delaying OS growth suggests that targeting JAK2/STAT3 may be a potential therapeutic strategy for patients with OS. STAT3-driven transcription is dependent on dimethylation of K49 by EZH2 functions as a co-activator for nuclear activity of RelB/p52 in positive regulation of pro-labor genes in the placenta Increased expression of STAT3 was associated with metastases in Colon Carcinoma. Pituitary adenoma GH hypersecretion is the result of STAT3-dependent GH induction, which in turn promotes STAT3 expression. Its signaling pathway plays a role in tumor angiogenesis. Genetic variants of STAT3 might contribute to anti-tuberculosis drug-induced hepatitis susceptibility in Chinese Han population. In this study, nifuroxazide not only decreased expression of Stat3 phosphorylation at tyrsione residue 705 but also downregulated MMP-2 and MMP-9 expression in 4T1 cells. Report diffuse expression of STAT3 in gastric adenocarcinomas. macrophages promoted BaP-induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-kappaB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Data show that calcitriol inhibited interleukin 6 (IL6) in association with an attenuation of STAT3 transcription factor activation. Constitutive activation of STAT3 is associated with myeloproliferative neoplasm. The role of STAT3 in tumorigenesis our findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway required to maintain the self-renewal and tumorigenicity of glioma stem-like cells. Aberrant STAT3 and HIF1a activity drives tumor progression in malignant peripheral nerve sheath tumors. PAR3-mutant proteins exhibit a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions and activate STAT3 at cell confluence. Jak1/Stat3 activation may mediate the activation of NF-kappaB and the expression of IL-8 in H. pylori-infected AGS cells. there is a regulatory pathway consisting of miR-30, SOCS3, and Jak/STAT3 in GSCs, and targeting this pathway may be a promising strategy to treat glioma. we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor Simultaneous silencing of beta-catenin and STAT3 synergistically induces apoptosis and inhibits cell proliferation in HepG2 liver cancer cells. active forms of STAT3 (pSTAT3) and GSK-3beta (pGSK-3beta) were found in 68 (25%) and 124 (46%) of 267 gastric cancer cases, respectively, showing a positive correlation (p < 0.001) SIRT1 and STAT3 expression protects retinal pigmented epithelium cells against oxidative stress. These findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status. Delta tocotrienol treatment inhibits ETK phosphorylation level and induces SHP-1 expression, which correlates with downregulation of STAT3 activation. Myricitrin treatment protects endothelial cells from ox-LDL-induced endothelial cell apoptosis, which results in reduced atherosclerotic plaque formation, via STAT3 signaling. MRTF-A and STAT3 synergistically recruited DNMT1 to hypermethylate the promoter of BRMS1 and affect the expression of BRMS1.MRTF-A and STAT3 promote breast cancer cell migration via hypermethylating BRSM1. Persistent activation of STAT3 by PIM2-driven positive feedback loop for epithelial-mesenchymal transition in breast cancer. Study demonstrates that HPV+ and HPV-head and neck squamous cell carcinoma(HNSCC) are differentiated by the activity of key transcription factors (TFs) including STAT3 and NF-kappaB. Approximately 25% of primary HNSCC, almost exclusively HPV-, have t [...] Findings suggest a crucial roles for resistin, IL-6 and STAT3 in breast cancer racial disparity. Capsaicin-induced apoptosis in pancreatic cancer cells was associated with inhibition of beta-catenin signaling due to the dissociation of beta-catenin/TCF-1 complex and the process was orchestrated by STAT-3. CD4 T cells from patients with RA have abnormal functional networks in STAT3 signaling and Wnt signaling. Data suggest that STAT Transcription Factors STAT1 and STAT3 defects have different effects on trained immunity. Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Endogenous PML suppresses interleukin (IL)-6-induced gene expression as well as phosphorylation and transcriptional activation of STAT3 in hepatoma cells. Identification of a novel tumor-promoting function for IGFBP2 of activating EGFR/STAT3 signaling and facilitating EGFR accumulation in the nucleus, thereby deregulating EGFR signaling by two distinct mechanisms. STAT3 and STAT5A were bound to the xCT promoter. Our results suggest the significance of STAT3 activation in the maintenance and survival of ovarian cancer cells Over-expression of IL-6 is correlated with hepatic dysfunction, variceal bleeding and p-STAT3 expression in cirrhotic patients. findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells USP22 attenuated the invasion capacity of colon cancer cells by inhibiting the STAT3/MMP9 signaling pathway. ferristatin II synergized with BMP6 and IL-6 to enhance hepcidin expression in vitro, However, this synergy was not due to activation of either Smad or Stat3 signaling Polymorphism in STAT3 gene is not associated with cervical cancer. miR-124 functions as a tumor suppressor in esophageal cancer through, at least partially, targeting STAT3 signaling pathway. weak RELA-activation signals (CD40L, LPS) depended on IFN-gamma induced STAT1/IRF1/IRF8 co-signalling, which was completely blocked by JAK inhibitors as reported before STAT3 signaling downstream of IL-23R and IL-21R has a role in controlling human mucosal-associated invariant T cells and NKT cell numbers we demonstrated that recombinant human OSM (rhOSM) promoted tumor angiogenesis in EC cell lines by activating STAT3 (signal transducer and activator of transcription 3) and enhanced both cell migration and cell inva STAT3 acts as a mediator that synergizes TGF-beta and Ras signals mutations result in hyper-IgE syndrome, which is treated by hematopoietic stem cell transplantation Mesenchymal Stem Cells Isolated From Human Gliomas Increase Proliferation and Maintain Stemness of Glioma Stem Cells Through the IL-6/gp130/STAT3 Pathway. we demonstrate the accumulation of granulocytic MDSCs with prostate cancer progression and the feasibility of using TLR9-targeted STAT3siRNA delivery strategy to alleviate MDSC-mediated immunosuppression These results show that temporarily increasing STAT3 activity is sufficient to reprogram human pluripotent stem cells to naive-like pluripotent cells. these findings indicate that constitutive IL6/STAT3 pathway activation is important in driving tumor growth and inflammatory cross-talk with myeloid cells within the Group A EPN microenvironment. Our study found that STAT3 rs4796793 polymorphism plays an important role in influence the development and overall survival of breast cancer patients. STAT3 inactivation reverses the glycolytic shift by down-regulating key enzymes and that it induces up-regulation of latexin as a tumor-suppressor molecule, which partially results in cancer cell apoptosis and tumor growth suppression. PTPRT promoter methylation is significantly associated with sensitivity to STAT3 inhibition in HNSCC cells, suggesting that PTPRT promoter methylation may serve as a predictive biomarker for responsiveness to STAT3 inhibitors in clinical development With the exception of one line of activated B cell Diffuse Large B Cell Lymphoma cells, the four variants were found in roughly the same ratios despite differences in total levels of STAT3 transcripts. The activation of Fas signaling promoted cell migration and resulted in STAT3-dependent Fascin upregulation in AGS gastric cancer cells. Protein and mRNA levels of PCBP2 were down-regulated under insulin-resistant conditions. Over-expression of PCBP2 inhibits HIF1alpha and STAT3 pathway. Phospho-STAT3 might be a prognostic factor of patients with digestive system cancers. results suggest that SIPAR terminates the activation of STAT3 through a dephosphorylation process that is dependent upon interaction with TC45 in the nucleus sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis activation of Src/STAT3/HO-1/autophagy signaling pathway might play a general role in protecting certain subtypes of breast cancer cells from doxorubicin-induced cytotoxicity Histone acetyltransferase inhibitor C646 reverses epithelial to mesenchymal transition of human peritoneal mesothelial cells via blocking TGF-beta1/Smad3 signaling pathway in vitro. miR-21 and let-7a function as clinically relevant integral components of STAT3 signaling. Lethe, which was upregulated by activated STAT3, may promoting the replication of HCV through a negative regulatory mechanism of type I IFN response. STAT3 phosphorylation is increased following overexpression of miR-155 in CD4+ T cells. meta-analysis suggests that the STAT3 rs12949918 and rs744166 polymorphisms, but not other three polymorphisms, may be an important protective factor for cancer Results suggest that STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in primary central nervous system diffuse large B-cell lymphoma Increased ADMA may lead to manifestation of pulmonary hypertension phenotype in human endothelial and smooth muscle cells via the STAT3/HIF-1alpha cascade. STAT3 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin and SRF. In arsenite-transformed HaCaT (HaCaT-30T) cells, down-regulation of STAT3 by siRNA blocked the process of epithelial-mesenchymal transition and decreased their neoplastic properties that were antagonized by over-expression of miR-21. Paeoniflorin inhibits cell viability and induces apoptosis through the up-regulation of miR-124 and suppression of PI3K/Akt and STAT3 signaling in gastric carcinoma cells. STAT3 signaling is a key element that regulates keratinocyte differentiation. The gp120-triggered modulation of miR expression via STAT3 activation. our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in cancer stem cell markers RPTS can significantly promote apoptosis in SW480 colorectal cancer cells. The mechanism may be that it suppresses the secretion of IL-6 and inhibits the IL-6/JAK-STAT3 protein signaling pathway. Expression analysis revealed upregulation of IL6 and CD126 and GP130 in ALDH(hi) endometrial cancer ... targeted inhibition of the IL6 receptor and its downstream effectors JAK1 and STAT3 reduced tumor cell growth. The protein expression of active caspase-3 increased with STAT3 siRNA treatment, and was significantly higher than that of the control group (P < 0.05). STAT3 gene-silencing significantly improves the apoptotic effect against Bel-7402 cells. gene deficiency is associated with vasculopathy Mice treated with STAT3 inhibitor galiellalactone had smaller primary prostate tumors and decreased lymph node metastases. Data show that both signal transducer and activation of transcription factors STAT5 and STAT3 were activated in significant percentages of cells in atypical ductal hyperplasia (ADH). cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting Glioblastoma stem cells ... targeting STAT3 signal pathway is an important strategy for the treatment of human glioblastoma multiforme B7H3 promotes cell migration and invasion through the Jak2/Stat3/MMP9 signaling pathway in colorectal cancer JAK2/STAT3 inhibitor AG490 inhibited the leptin-induced migration, invasion and MMP-2 expression in endometriotic cells. Leptin does this via the up-regulation of MMP-2 through an ObR-dependent JAK2/STAT3 signaling pathway. Our results suggested that STAT3 phosphorylation is involved in PLCe-mediated inflammatory cytokine release STAT3 activation may induce invasion and metastasis through the mediation of epithelial-to-mesenchymal transition in hepatocellular carcinoma cells. Single Nucleotide Polymorphism rs1053004 in STAT3 gene is associated with Susceptibility to Hepatocellular Carcinoma with Chronic Hepatitis B. These results suggest that STAT3 inhibition, by down-regulating the expression of HSF1/HSP70, reduces Mcl-1 and leads to both apoptosis and autophagy induction in PEL cells. Study demonstrate that STAT3 rs744166 G allele is associated with increased risk of gastric cancer in a Western population. Mutations leading to constitutive active gp130/JAK1/STAT3 pathway. miR-204 targets JAK2 and suppressed JAK2 and p-JAK2 expression in breast cancer, which further inhibit the activation of STAT3, BCl-2 and survivin. Glycyrrhizic acid inhibits leukemia cell growth/migration by blocking AKT/mTOR/STAT3 signaling. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. Both studied polymorphisms in the STAT3 gene seem to play a significant role in susceptibility to Hashimoto's thyroiditis (HT) and Graves' disease. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive breast cancer Increased expression of SgK223 occurs in PDAC, and overexpression of SgK223 in pancreatic ductal epithelial cells promotes acquisition of a migratory and invasive phenotype through enhanced JAK1/Stat3 signaling Positive expression of pSTAT3 is associated with poor prognosis in gastric cancer patients.[review; meta-analysis] The present study therefore demonstrated that 2-alkyl substituted quinazolines target the JAK2/STAT3 pathway for their antitumor activity Activation of c-Src/STAT3 signaling by Ceacam1L is a crucial factor in glioblastoma-initiating cell maintenance and tumorigenesis. Monomers of the cytoplasmic domain of Ceacam1L bound to c-Src and STAT3 and induced their phosphorylation. Study showed low expression level of miR-519d associated with TNM staging and metastasis of breast cancer, and suggested it as a tumor suppressor with role in breast cancer cell proliferation and invasion by downregulating STAT3. Data provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA. BCL-XL up-regulation by STAT3 contributes to mutant KRAS-mediated apoptosis resistance. Such resistance can be overcome by potent BIM induction and concurrent BCL-XL antagonism G6PD may function as an important regulator in development and progression of esophageal squamous cell carcinoma by manipulating STAT3 signaling pathway RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway. Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15-activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-alpha. Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in pancreatic ductal adenocarcinomas. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC by controlling a fundamental step in CD1d-mediated lipid antigen presentation, STAT3 signalling promotes innate immune responses driven by CD1d Increased IL10, not IL4 or IL13, in senescent eyes activates STAT3 signalling that induces the alternative activation of macrophages and vascular proliferation. ATR is down-regulated by STAT3-regulated microRNA-383 in A431 cells. suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors IL-17 induced STAT3 activation as a necessary step in endothelial cell activation and neutrophil recruitment. These data uncover a synthetic lethal interaction involving glutathione production and mitochondrial reactive oxygen species regulation in Ras-transformed cells that is governed by mitochondrial STAT3 and might be exploited therapeutically. the STAT3 mutations found in the patient cohort were concluded to be deleterious for normal STAT3 function. Single Nucleotide Polymorphisms in STAT3 is associated with Hand-Foot Skin Reactions in Patients with Metastatic Renal Cell Carcinoma Treated with Multiple Tyrosine Kinase Inhibitors. STAT3 binding assays revealed a significant STAT3 inhibitory activity and selectivity versus Grb2 for one of the four top-scored compounds, thus verifying the reliability of the virtual screening workflow STAT3 and miR-21 are cooperative regulators of stemness, migration and tumor initiation in lung-derived brain metastasis Data suggest the therapeutic potential of microRNA miR-23a/interleulin-8 (IL-8)/Stat3 protein (Stat3) signaling axis in nasopharyngeal carcinoma (NPC). radiosensitization. MiR-129-5p may directly inhibit STAT3 expression. Silencing Beclin1 in HTLV-1-transformed T cells resulted in diminished activities of NF-kappaB and Stat3 as well as impaired growth. IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. The positive expression rate of STAT3 was higher in breast cancer tissue compared to normal breast tissue, which was correlated with clinical stage, tumor differentiation, and lymph metastasis. Data indicate that box protein 1, high mobility group (HMGB1) could regulate the expression of STAT3 transcription factor by modulation of its DNA methylation in CD4(+) T cells. Applying chromatin immunoprecipitation (ChIP) technique and luciferase assay, we further approved that FoxM1 can transcriptionally active signal transducer and activator of transcription 3 (STAT3), ensuring normal HESC differentiation. high levels of STAT3 correlate with the refractory state at the single-cell level under conditions of both spontaneous and induced lytic activation; importantly, STAT3 also regulates lytic susceptibility. The results of the present study clearly demonstrate that the STAT3 pathway triggered by anti-inflammatory IL-27 plays a role in protecting cardiomyocytes against GSC-mediated damage. These findings underscore the importance of understanding the complex interactions between PR and other regulatory factors, such as Stat3, that contribute to determine the context-dependent transcriptional actions of PR. HES5 knockdown resulted in the reduction of p-STAT3 onstitutive STAT3 phosphorylation in circulating CD4+ T cells is common in recent-onset untreated RA and associates with good treatment response in patients characterized by high disease activity and the presence of systemic inflammation Placental endothelial cell-derived PDGF-BB recruits human placental multipotent mesenchymal stromal cells involved in vascular development via PDGFR-beta/STAT3 activation PAFR stimulated EMT by activating STAT3 via upregulation of G-protein-dependent SRC or JAK2 kinase activity. STAT3 transcriptionally elevated PAFR expression. A forward feedback loop between PAFR and STAT3 drives the malignant progression of NSCLC. Increased STAT3 activation during immune responses. IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1. The level of miR-21 expression positively related to the expression of PDCD4 protein and negatively related to the expression of p-STAT3 protein in salivary adenoid cystic carcinoma specimens. SOX2 Promotes the Epithelial to Mesenchymal Transition of Esophageal Squamous Cells by Modulating Slug Expression through the Activation of STAT3/HIF-alpha Signaling GP130/STAT3 signaling contributes to the resistance of these drugs in rhabdomyosarcoma cells. GCN5 Potentiates Glioma Proliferation and Invasion via STAT3 and AKT Signaling Pathways Data show that crizotinib can induce cytoprotective autophagy by suppression of STAT3 transcription factor in lung cancer cells. increased expression in placental endothelial cells associated with pre-eclampsia data suggest that STAT3 contributes to NK cell recognition by modulating NKG2D ligands in K562/AO2 cells, which may a mechanism by which cells survive and cause relapse of leukemia. MiR-125a suppresses cervical tumor growth, invasion and metastasis by targeting STAT3. by molecular docking analysis and tumor sphere assay we discover that curcumin was able to inhibit JAK2 activity and reduce tumor spheres via inhibiting the JAK2/STAT3 signaling pathway the present study demonstrated that Fzd2 contributes to the migration and invasion of OSCC cells, at least partly through regulation of the STAT3 pathway we have presented data supporting that STAT3beta is a tumor suppressor in ESCC, and STAT3beta can effectively suppress the oncogenic effects of STAT3alpha Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection. findings strengthen the evidence for a central role of STAT3 in the pathogenesis of LGL leukemia. Subsequently, the importance of screening the entire STAT3 gene in the diagnostic workup of LGL leukemia, as well as in other lymphoid malignancies wher [...] miR-125a-5p directly targets IL-6R and STAT3 expression in HEK-293T cells. potential utility of a signature involving Bcl-2 overexpression, Rac1 activation and STAT3 phosphorylation for stratifying clinical lymphomas based on disease severity and chemoresistance in patients with hyper-IgE syndrome, mutations lead to impaired Th17 cell numbers Letter: Interleukin-22 inhibits tazarotene-induced gene 3 expression in keratinocytes via MAPK-ERK1/2 and JAK2/STAT3 signaling. SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus miR-125b modulates PCT expression by manipulating the amount and transcriptional activity of Stat3. The human monocytes are predisposed to differentiate towards an macrophage activation program characterized by the CD16(+)CD163(+)MerTK(+)pSTAT3(+) phenotype and functional properties such as enhanced protease-dependent motility, and immunomodulation. Our study indicates that apigenin induces apoptosis through inhibition of STAT3 signalling and could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer. These results indicated that the coordinated recruitment of STAT3, CREB-1, and GR to the promoter of the gene encoding COX-2 contributes to the feed-forward induction of COX-2 activity and prostaglandin synthesis in the amnion during parturition. Paeoniflorin induced growth suppression and apoptosis in human glioma cells through the proteasome-dependent degradation of STAT3. we demonstrate that M. tuberculosis infection leads to downregulation of miR-17 and concomitant upregulation of its targets Mcl-1 and STAT3, a transcriptional activator of Mcl-1. Forced expression of miR-17 reduces expression of Mcl-1 and STAT3 and a [...] Data indicate the role of tropomyosin-related kinase-B (TrkB) in activation of the interleukin-6/Janus kinase 2/STAT3 transcription factor and PI3 kinase/c-AKT proto-oncogene protein pathway in breast cancer. miR-21 in exosomes leads to STAT3 activation, which increases VEGF levels in recipient cells, a process involved in angiogenesis and malignant transformation of human bronchial epithelial cells PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. These findings support the notion that salinomycin may be potentially efficacious for targeting breast cancer stem-like cells through the inhibition of STAT3 activation. MicroRNA-29a promotes apoptosis of monocytes by targeting STAT3 during sepsis The activation of STAT3 by nuclear PKM2 was associated with gefitinib resistance. data show decreased nuclear accumulation and transcriptional activity of STAT3 in PAK4-silenced pancreatic cancer cells lack of p21 has catabolic effects by regulation of aggrecan and MMP-13 expression through STAT3 phosphorylation in the cartilage tissue pimozide reduced the basal expression of phosphorylation STAT3 at tyrosine 705 and reversed the expression of phosphorylation of STAT3 induced by IL-6 addition, suggesting that pimozide can suppress cellular STAT3 activation these data indicate that IL-6 inhibits starvation-induced autophagy and that p-STAT3 mediates the signal transduction from IL-6 to downstream proteins including Bcl-2 and Beclin1 Our data suggest that miR-21 expression is increased in breast cancer and plays an important role as a tumor gene by targeting STAT3, which may act as a double-response controller in breast cancer. STAT3 linker domain mutants to have profound effects of inhibiting STAT3 transcriptional activation. Blockade of p-STAT3 in combination with conventional chemotherapeutic drugs improves cancer stem cell eradication in head and neck squamous cell carcinoma. This review provides a full spectrum of STAT3's involvement in breast cancer by consolidating the knowledge about its role in breast cancer development MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistic [...] Studies indicate that cadherins mediate cell to cell interactions are potent activators of the signal transducer and activator of transcription 3 (Stat3), thereby offering survival signaling. N225K and A550V PTPN6 mutations cause loss-of-function leading to JAK3 mediated deregulation of STAT3 pathway and uncover a mechanism that tumor cells can use to control PTPN6 substrate specificity. We determined that IL-17A-induced VEGF upregulation and neovascularization through a Stat3-mediated signaling pathway and hypothesized that blocking the Stat3 activation by using JSI-124, an inhibitor of phosphorylated Stat3, could significantly redu [...] Antisense oligonucleotide AZD9150 decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. These results suggest the downregulation of miR-98 could promote Intervertebral Disc Degeneration through the IL-6/STAT3 signaling pathway. comparative study provides a long-term observation of DOCK8- and STAT3-hyper-IgE syndrome patients with regard to clinical and laboratory findings, and assesses the activation and cytokine secretion of lymphocytes after in vitro stimulation Data show that signal transducer and activator of transcription-3 (STAT-3) activation occurs downstream of leukotriene B4 receptor-2 (BLT2) and mediates cisplatin resistance in SK-OV-3 cells. a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation. In conclusion, rheumatoid arthritis synovial fibroblasts were activated by CXCL16 to produce RANKL via pathways involving JAK2/STAT3 and p38/MAPK Suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors in renal cell carcinoma. Psoriatic Tregs experience a predominant STAT3 phosphorylation by exposure to pro-inflammatory cytokines, leading to their impaired functions in suppressing activation of responder T cells . Pivotal biological functions of STAT3 in cancer:STAT3 promotes cancer through altering gene expression via epigenetic modification, inducing epithelial-mesenchymal transition phenotypes in cancer cells Data show that morusin is a blocker of signal transducer and activator of transcription 3 (STAT3) activation and thus may have potential in negative regulation of growth and metastasis of pancreatic tumor cells. our data suggest that SIRT6 suppresses glioma cell growth via induction of apoptosis, inhibition of oxidative stress and inhibition of the activation of the JAK2/STAT3 signaling pathway. Increased STAT3 phosphorylation is associated with Colorectal Cancer. IL-6 stimulation leads to STAT3 activation. Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers, we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo STAT3 inhibition in spheroids generated from the established cancer cells and primary glioblastoma patient-derived cells altered the rounded morphology and increased drug sensitivity. Our results suggest that NFkappaB, STAT1 and STAT3 underlie transcriptional changes and chronic inflammation in the aging human kidney HSP90 inhibitor ganetespib inhibits pancreatic cancer cell proliferation via JAK2/STAT3 pathway. A novel role of STAT3/miR-21 axis and CDK5/CDK5R1 (p35) in metastasis of head and neck squamous cell carcinoma. Our findings provide a novel link among Stat3/5 signaling and MDS pathobiology and suggest that the Stat3/5 signaling biosignature may serve as both a response biomarker and treatment target. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Treatment of isolinderalactone increased the protein level of SCOS3, decreased phosphorylation of the STAT3 and suppressed expression of the down-stream genes of the X-linked inhibitor of apoptosis protein SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis. This study concluded that the IL-6/STAT3 pathway regulates the pancreatic stellate cell-induced epithelial-mesenchymal transition and alterations in gene expression in pancreatic cancer cells. The link of high glucose and STAT3 activation was confirmed in tumor tissues from cholangiocarcinoma patients with diabetes mellitus that exhibited higher STAT3 activation than those without diabetes mellitus. Our data suggested that IL-6 mediates the singnal pathway of JAK-STAT3-VEGF-C promoting the growth, invasion and lymphangiogenesis in gastric cancer nuclear localization of pSTAT3 in leukemic cells may have a role in hematopoietic stem cell transplant-associated large granular lymphocytic leukemia High STAT3 expression is associated with radioresistance in HER2-positive breast cancers. High STAT3 expression is associated with osteosarcoma. Cytokine levels contribute to the pathogenesis of minimal hepatic encephalopathy in patients with hepatocellular carcinoma via STAT3 activation Hyperactivated STAT3 is associated with Inflammatory and Invasive Ductal Breast Cancers. This study discovered allosteric communications between STAT3 domains. colorectal cancer cells secreting IL-6 via STAT3 phosphorylation can enhance the phagocytic capacity and migration of macrophages in the tumor microenvironment. The endometrium of women with dormant genital tuberculosis is associated with poor receptivity, as evidenced by aberrant LIF-STAT3 signaling. activation of STAT3 may play an important role in the acquisition of resistance to gemcitabine and HER inhibitors in pancreatic cancer Our data indicated that Eag1 promotes osteosarcoma proliferation and migration, at least in part, by targeting STAT3-VEGF pathway. The STAT3-Ser/Hes3 Signaling Axis was first identified as a major regulator of neural stem cells and, subsequently, cancer stem cells High expression of STAT3 is associated with cutaneous T-cell lymphoma. Stat3 was correlated with NANOG-mediated EMT. Ceramide induced the binding of STAT3, but not NF-kappaB or c-Jun, to HAMP promoter. Inhibition of STAT3 with a pan-JAK kinase inhibitor and STAT3 siRNA pool also diminished the induction of both HAMP promoter activity and mRNA expression by ceramide. lnc-DILC mediates the crosstalk between TNF-alpha/NF-kappaB signaling and autocrine IL-6/STAT3 cascade and connects hepatic inflammation with liver cancer stem cells expansion. High STAT3 expression is associated with leukemia. High STAT3 expression is associated with colon cancer. In conclusion, our data suggested that CAFs could activate the anti-apoptotic STAT3 signaling, thereby decrease the Cisplatin-induced apoptosis and promote chemoresistance in ovarian cancer. The rs4796793 STAT3 genotype is a novel predictive factor for response to multiple tyrosine kinase inhibitors in metastatic renal cell carcinoma. ANOG was regulated by extracellular IGF signaling pathway via STAT3 phosphorylation in colorectal cancer (CRC). This coincides with that IGF receptor IGF-1R is often increasing expressed in malignant metastasis colon cancer. Taken together, our data [...] the increased p-stat3 expression may be not only predict poor prognosis, but also be associated with worse tumor differentiation and lymph node metastasis in patients with gastric carcinoma. HSP72 blocks fibroblast activation and proliferation in renal fibrosis via targeting the STAT3 pathway and may serve as a novel therapeutic agent for chronic kidney disease regardless of the etiology silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. High glucose upregulates IL-6 synthesis in mesothelial cells, to some extent, depending on its osmolality and that IL-6 trans-signalling could induce VEGF synthesis partly dependent on the JAK/STAT3 pathway. miR-874 functions as a tumor suppressor by repression of STAT3 in human colorectal cancer cells Rhus coriaria inhibited angiogenesis, reduced VEGF production in both MDA-MB-231 and HUVECs and downregulated the inflammatory cytokines TNF-alpha, IL-6 and IL-8. The underlying mechanism for Rhus coriaria effects appears to be through inhibiting NFk [...] STAT3 expression is upregulated in both HBV- and HCV-related hepatocellular carcinoma (HCC), while hexokinase II (HK-II) is predominantly upregulated and correlated to STAT3 in HBV-related HCC PASD1 serves as a critical nuclear positive regulator of STAT3-mediated gene expression and tumorigenesis. The present study finds that the aspirin-FOXD3-OLA1P2-STAT3 axis exhibits exciting anticancer effects and provides new insights into the chemopreventive mechanisms underlying aspirin use Results show that nuclear pSTAT3 expression was associated with improved patient outcome with breast cancer while less pSTAT3 was found in tumors from patients developing metastasis. STAT3 seems to act as a tumor suppressor. Data indicate strategies to improve the effectiveness of EGFR inhibition particularly by blocking the STAT3 pathway. Helicobacter pylori-induced STAT3 activation is mediated, at least in part, through reactive oxygen species-induced upregulation of IL-6 expression. results suggest that the activation of the IL6/STAT3 pathway in tumor cells may provide a survival advantage during anti-VEGF treatment, suggesting its utility as a source of response biomarkers and as a therapeutic target to heighten efficacious results UT2 is a negative regulator shared across STAT3 and mTORC2 signaling cascades, functioning as a tumor suppressor in hematologic malignancies driven by those pathways. Genetic Variation in the STAT3 gene is associated with distal Colonic Disease, Stricturing Disease Behavior. Imatinib-resistant K562/G01 cells expressed significantly higher levels of STAT3 and RPS27a compared with those of K562 cells. Results show that IFN-alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus (HCV )and that STAT3 regulation correlates inversely with SOCS3 induction by IFN-alpha, which may be important in better understanding the complex interp [...] STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions, thus permitting vascular permeability. fad104 suppressed anchorage-independent growth of melanoma cells, and the N-terminal region of FAD104 is essential for inhibiting malignant transformation and STAT3 activity Elevated transcription proteins 3 (STAT3) expression is associated with poor survival in most solid tumors, suggesting a valuable biomarker for prognosis prediction and a promising therapeutic target. results suggest that IL10-mediated inhibition of autophagy is facilitated by the cross talk between STAT3, AKT, and mTOR; in other words, the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways. this study proposes that inflammation-induced Jak-STAT3 signaling leads to colon cancer development through proteasomal degradation of DICER1 by ubiquitin ligase complex of CUL4A(DCAF1), which suggests a novel therapeutic opportunity for colon cancer 17beta-estradiol enhances the expansion and activation of myeloid-derived suppressor cells via STAT-3 signaling in human pregnancy. Intracellular p19 associated with the cytokine receptor subunit gp130 and stimulated the gp130-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling phosphorylation of STAT3 and AKT was highly induced by treatment with IL-22 via IL-22R1. IL-22R1 was also consistently overexpressed in recurrent NSCLC tissues The ROCK2-inhibitor KD025 decreases STAT3 phosphorylation in human peripheral blood mononuclear cells from cGVHD patients. STAT3 plays an important role in IFN-induced A3G production, and HBsAg may correlated with poor response to IFN treatment results have proven that IL-12-overexpressed monocytes could directionally differentiate to M1-like macrophages through downregulation of Stat-3 and result in the inhibition of HCC growth These results suggest that miR146a may regulate SOCS1/STAT3 and cytokine signalling in monocytes, directing T-cell differentiation and balancing immune clearance and immune injury during chronic viral infection. STAT3 activation in circulating monocytes may contribute to the development of choroidal neovascularisation in Age-Related Macular Degeneration. In patients with glioblatoma, tumors which exhibited greater nuclear localization of STAT3 corresponded with patients that presented with lower rates of recurrence-free survival and overall survival. signal transducer and activator of transcription 3(STAT3) and zinc finger E-box binding homeobox 1(ZEB1) could be the key molecules altered at the early stages of carcinogenesis, especially in high-grade prostatic intraepithelial neoplasia Our results support an important association of rs744166 and rs4796793 in STAT3 with decreased Crohn's disease risk, and additional interaction between rs744166 and smoking Data suggest that STAT3 signaling plays pivotal roles in regulating function of multiple cell types in skeletal muscle. In muscle stem cells, STAT3 antagonizes self-renewal; in myofibers, STAT3 regulates skeletal muscle mass; in activated macrophages [...] CADM1 prevents squamous cell carcinoma progression by reducing STAT3 activity ASC-J9((R)) could suppress prostate carcinoma stem cell invasion via altering the EZH2/STAT3 and/or AKT/EZH2/STAT3 signals. These results indicate that ARL3 interacts with STAT3 and regulates the transcriptional activation of STAT3 by influencing its nuclear accumulation of STAT3. We found that a significant higher gastric cancer risk was associated with IL-6 rs2069837G variant genotypes and JAK1 rs2230587A variant genotypes Data show that IKKalpha directly bind to the promoters of LGR5, in turn, upregulating LGR5 expression through activation of STAT3 signaling pathway during cancer progression. Data show that Rac1 induced nuclear import of STAT3 by physical binding, and nuclear STAT3 directly activated the transcription of essential oocyte-specific genes, including Jagged1, GDF9 and BMP15. Data show that the activation of STAT3 protein upregulated human cervical cancer oncogene (HCCR) expression in gastric cancer cells. Piperlongumine reduced the phosphorylation of Janus kinase (JAK)1, JAK2 and signal transducer and activator of transcription (STAT)3 in a concentrationdependent manner large granular lymphocyte leukemia patients with STAT3 SH2 domain mutations showed significantly smaller cells compared with patients without STAT3 mutations. This small subtype of T-LGL-L was recognized among rather young patients and was associated [...] inflammatory cytokine insults stimulate epithelial-to-mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3-dependent NGN3 activation. The sensitivity of chronic lymphocytic leukemia cells to in vitro spontaneous apoptosis is co-regulated by constitutively activated STAT3 and NF-kappaB and reflects the in vivo chemo-responsiveness and clinical outcomes. When STAT3 levels were sufficiently high, STAT3 no longer protected chronic lymphocytic leukemia (CLL) cells from apoptosis. Instead, STAT3 induced the expression of proapoptotic genes, activated the caspase-3 gene promoter, and induced apoptosis in [...] Docosahexaenoic acid inhibits STAT3 activation by inducing PPARgamma-mediated SOCS3 transcription in the Helicobacter pylori infected human gastric cancer cells. The IL-34/STAT3/miR-21 pathway is crucial for the survival of synovial fibroblasts in rheumatoid arthritis HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic ductal adenocarcinoma. study provided the first evidence that B7-H4 facilitated esophageal squamous cell carcinoma cell proliferation through promoting IL-6/STAT3 positive loopback pathway activation Taken together, these findings suggested that E2 inhibited the proliferation of AR HCC cells through down-regulation of IL-6/STAT3 signaling. Thus, E2 can be a potential therapeutic drug for treatment of metastatic or chemo-resistant HCC. a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity, is reported. Data indicate that EPHA3 is involved in regulating the multidrug resistance (MDR) of small cell lung cancer (SCLC) via PI3K/BMX/STAT3 signaling and may be a therapeutic target in SCLC. over-expression of GRIM-19 and silencing of STAT3 both increased lactate production in H9C2 cells STAT3 signaling pathway may reverse anoikis resistance and prevent metastasis in cholangiocarcinoma. Data show that secretion of IL-6 induced by loss of HIC1 activated STAT3 through IL-6/JAK pathway and was associated with NSCLC progression. Impairment of TGF-beta signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in interstitial pneumonia in connective tissue, and to myofibroblast differentiation in usual i [...] Oleanolic acid markedly suppressed the activation of the STAT3 and SHH signaling pathways and inhibited the expression of the proangiogenic vascular endothelial growth factor A and basic fibroblast growth factor, two important target genes of the afo [...] Melatonin inhibits tumorigenicity of glioblastoma stem-like cells via the AKT-EZH2-STAT3 signaling axis. Treatment with Tetrandrine (TET) resulted in downregulation of phosphorylated NFkappaB p65 and reduction of the production of TNFalpha and IL1beta. In addition, the phosphorylation of ERK and STAT3 was decreased by TET in activated macrophages. Down-regulation of the STAT3 signaling pathway mediates thymoquinone induced apoptosis in gastric cancer. Immunohistochemical analysis showed that STAT3, GRP78 and BAX protein levels in the combination group were significantly higher than those in STAT3 group and CDDP group (P<0.05). Exogenous STAT3 and CDDP may synergistically inhibit the xenograft tumo [...] Data show that tight junction protein 1 (TJP1) suppressed expression of the catalytically proteasome subunits LMP7 and LMP2, decreased proteasome activity, and enhanced proteasome inhibitor sensitivity in vitro and in vivo through suppression of EGFR [...] This study reveals STAT3 mRNA localization at the cell protrusions of metastatic hepatocellular carcinoma HCCLM3 cells by combining application of genome-wide and gene specific description and functional analysis. Data suggest that the BRG1/STAT3/VEGFC in tumor-associated lymphangiogenesis might lead to the discovery of novel therapeutic targets in the treatment of cancers with BRG1 loss of function. this study shows that Hepatitis C virus-induced myeloid-derived suppressor cells promote regulatory T cell development and inhibit effector T cell function via the STAT3 pathway, representing a novel mechanism for T-cell regulation during viral infection Data indicate a strong positive correlation between interleukin-1 receptor-associated kinase 3 (IRAK-M) and pSTAT3 protein in colorectal cancer (CRC). miR551b-3p binds a complementary sequence on the STAT3 promoter, recruiting RNA polymerase II and the TWIST1 transcription factor to activate STAT3 transcription, and thus directly upregulates STAT3 expression. Identify Kaposi sarcoma virus miR-K12-1 as an oncogene which activates NF-kappaB/IL-6/STAT3 signaling pathway, promoting tumorigenesis. Mitochondrial GRIM-19 could not only serve as an valuable prognostic biomarker for Gastric cancer development, but also as a potential therapeutic target for STAT3-dependent carcinogenesis of Gastric cancer. Data show that miR-222-3p targeted SOCS3 genes and down-regulation of SOCS3 correlated with an increased expression of STAT3 activation. Together, these results suggest that the IL-11/STAT3 signaling pathway plays a critical role in human chronic atrophic gastritis , and may provide new targets to prevent and treat gastric cancer The balance between IL-2-induced STAT5 activation, regulated by TCR signaling, and STAT3 activation, regulated by pro-Th17 cytokines, is likely to be critical in determining the level of Th17 polarization. HCV NS4B contributed to hepatocellular carcinoma by activating the endoplasmic reticulum stress-mediated cancer-related STAT3 pathway. Our data identified SUMOylation as a previously undescribed post-translational modification of STAT3 and SENP3 as a critical positive modulator of tobacco- or cytokine-induced STAT3 activation. phosphorylated Hsp27 stimulates autophagy and lipid droplet clearance and interacts with STAT3. SEYG extract has the potential source of STAT3 inhibitors. Here, we attempt to summarize information on the numerous and distinct biological actions of STAT3, and highlight recent discoveries, with a specific focus on STAT3 function in the immune and hematopoietic systems. MicroRNA-544 down-regulates both Bcl6 and Stat3 to inhibit tumor growth of human triple negative breast cancer IL-10 stimulation activated the JAK/Stat-3 and PI3K/Akt signaling pathways. Moreover, IL-10 treatment increased translocation of p65 NF-kappaB into the nuclear compartment, and up-regulated expression of the pro-survival proteins Bcl-2 and Bcl-xL. STAT3 and miR-181b control each other's expression in a positive feedback loop that regulates SFCs via CYLD pathway. STAT3/STAT1 ratios are better clinical predictors in Colorectal carcinoma as compared to STAT3 or STAT1 levels alone. Cdk4 inhibition leads to directing human mesenchymal stem cells to a multipotent neurogenic fate by inactivating Smads-STAT3 signaling. STAT3 overexpression is associated with Breast Cancer. High STAT3 expression is associated with melanoma. we have identified acquired activating mutations in JAK1 and STAT3 in two cases of effusion-limited BIA-ALCL and identified a possible contribution to disease development from a germline JAK3 variant. role of heat shock protein 90 in leptin-induced STAT3 activation and feeding regulation Results show that STAT3 activation is mediated by Pyk2 for hypoxia-induced retinal neovascularization and for VEGFA-induced human retinal microvascular endothelial cell migration, sprouting and tube formation. hypoxia induces epithelial-mesenchymal transition of esophageal squamous cell carcinoma, and STAT3 regulates this process by promoting HIF-1alpha expression. The blood coagulation pathway may be a key regulatory network pathway contributing to the allergic inflammatory response in AR patients. A2M, which is regulated by STAT3, may be an important protein in the pathogenesis of allergic rhinitis in AR patients. STAT3/miR-182-5p/PCDH8 axis has a critical role in glioma tumorigenesis. Results indicate that the IL-6/STAT3/NF-kappaB positive feedback loop includes AUF1 and is responsible for the sustained active status of cancer-associated fibroblasts. Data show that MLLT11/AF1q-induced PDGFR signaling enhanced STAT3 activity through Src kinase activation. Cyclosporine A dramatically increased gefitinib-induced apoptosis in primary sensitive, primary resistant and acquired resistance non-small cell lung cancer cells viat STAT3 inhibition. a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT protein family which forms a homo- or heterodimer that translocates to the cell nucleus where it acts as a transcriptional activator to inhibit apoptosis in various ca [...] Results found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells and suggest that STAT3 is necessary for ovarian tumor progression/metastasis. cancer associated fibroblasts (CAFs) promoted hepatocellular cancer (HCC) growth via IL-6/STAT3/AKT pathway and TIMP-1 over-expression driven by IL-6/STAT3 pathway in HCC cells brought in more CAFs through activating liver fibroblasts. Leukemia inhibitory factor (LIF) - STAT3 transcription factor (STAT3) signaling pathway is systemically dysregulated in in the endometrium of patients with recurrent/repeated implantation failure (RIFE). Suspension survival mediated by PP2A-STAT3-Col XVII determines tumor initiation and metastasis in cancer stem cells. Elucidating the effects of disease-causing mutations on STAT3 function, phosphorylation and dimerization in autosomal-dominant hyper-IgE syndrome. Overexpression of Msi2 significantly increased and silencing of Msi2 reduced the phosphorylation of JAK2 and its downstream effecter STAT3. these results suggest that 3-Formylchromone is a novel blocker of STAT3 activation pathway thus may have a potential in therapy of MM and other cancers. Authors confirmed that STAT3 activation by IL-6 regulates MSCs-induced chemoresistance. Valosin-containing protein (VCP) promotes the growth, invasion, and metastasis of colorectal cancer through activation of STAT3 signaling. Data suggest that the platelet derived growth factor receptor alpha (PDGFRalpha)/Stat3 transcription factor/Rb1 protein regulatory axis might represent a potential therapeutic target for glioblastoma (GBM) treatment. STAT3 mRNA and protein levels were higher in bone than in lymph node and visceral metastases of castration-resistant prostate cancer. Distinct mutations at the same positions of STAT3 cause either loss or gain of function. Our results showed that DOCK8-deficient patients have a profound defect in TH17 differentiation related to decreased STAT3 phosphorylation, translocation to the nucleus, and transcriptional activity Data indicate that microRNA miR-410 is the key regulatory factor in the pathogenesis of systemic lupus erythematosus (SLE) by regulating the expression of IL-10 through targeting STAT3. Data show that interleukin-12 (IL-12) treatment decreased the expressions of p-AKT protein, p-mTOR protein and p-STAT3 protein. Data show that the expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2 increased in the combined hypoxia and TNF-alpha treatment group. Data show that the expressions of p-JAK2 protein and p-STAT3 protein were down-regulated after treated with Interferon-beta (IFN-beta) combined with all-trans retinoic acid (ATRA) on HepG2 cells, especially the combination of IFN-beta and ATRA. Data show that astaxanthin functions as a potent inhibitor of A549 lung cancer cell growth by targeting Janus kinase 1 a(JAK1)/STAT3 transcription factor (STAT3) signaling pathway. Data show that knockdown of signal transducer and activator of transcription (STAT3)- significantly inhibited the mRNA and protein levels of survivin. The inhibition of STAT3 is detrimental for M. tuberculosis intracellular replication. Taken together, pretreatment with RA suppressed high glucose-induced apoptosis in cardiomyocyte by ameliorating mitochondrial function and activating STAT3. Findings indicate the importance of Src-Stat3 signaling cascade in gallic acid (GA)-mediated tumor-suppression activity and a therapeutic insight of GA for acquired resistance to EGF receptor tyrosine kinase inhibitors in lung cancer. the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel these data suggest that ROCK2 signaling plays a critical role in controlling the development of TFH cells induced by autoimmune conditions through reciprocal regulation of STAT3 and STAT5 activation. found that USP6 directly deubiquitinated Jak1, leading to its stabilization and activation of STAT3 hTFF3 exhibits self-induction action, and that STAT3 is the key transcription factor to maintain the function of self-induction. Molecular modelling studies of PAK1 with its major interacting partners RHOA and STAT3 revealed potential network gene elements in breast invasive carcinoma. Huaier aqueous extract inhibited JAK2/STAT3 and MAPK signaling pathways. MiR-451 may function as a potential suppressor of tumor angiogenesis in HCC by targeting IL-6R-STAT3-VEGF signaling, suggesting. Schistosoma japonicum egg antigen p40 through action on the STAT3/p53/p21 pathway triggered cellular senescence, while knockdown of p53 or STAT3 partly restored cell senescence. Dihydromyricetin (DHM) increased the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3)-dependent autophagy by generating reactive oxygen species (ROS)-signaling pathways in head and neck squamous cell carcinoma. designed, synthesized and evaluated 1,4-dimethyl-carbazole derivatives, targeting the STAT3 protein. Moreover, MTT assay performed on A375 and HeLa, showed significant antiproliferative activity of some of synthesized compounds (3-5). The same compou [...] a requirement for IL-10-dependent autocrine activation of the STAT3 pathway, is reported. IL-22 protects against sodium nitroprusside-induced apoptosis in rheumatoid arthritis-fibroblast-like synoviocytes by activating the STAT3 pathway and the downstream target gene, Bcl-2. CD24 induced colorectal cancer angiogenesis in Hsp90-dependent manner and activated STAT3-mediated transcription of VEGF. The present study demonstrated that the downregulation of filaggrin in the epidermis by toluene is mediated by ERK1/2 and STAT3-dependent pathways. p-STAT3 overexpression is unfavorable for the prognosis of colorectal cancer patients Our data suggest an important role of beta2-AR/STAT3/miR-373 signaling on the transformation of gastric cancer cells. High stat3 expression is associated with Gastric Cancer. CD44 and CD24 collaboratively drive the reprogramming of nasopharyngeal carcinoma cells through STAT3-mediated stemness and epithelial-mesenchymal transition activation STAT3 bound to the 5' upstream sequence (-1971 to -1964), a putative promoter region, of WDR1 gene, and its activation induced WDR1 overexpression in breast cancer cells. High STAT3 expression is associated with nasopharyngeal cancer. triacetylresveratrol (TRES), similarly to Resveratrol (RES), inhibited the phosphorylation of STAT3 and NFkappaB, down-regulated Mcl-1, and up-regulated Bim and Puma in pancreatic cancer cells. Remarkably, we, for the first time, observed that both T [...] G-rich sequences in the STAT3 gene could form G-quadruplexes under near physiological conditions. The expression level of Sox4 correlates with HCC development, clinical severity and prognosis of patients. LncSox4 interacts with and recruits Stat3 to the Sox4 promoter to initiate the expression of Sox4, which is highly expressed in liver tumor-ini [...] bladder cancer cell may inhibit maturation and function of dendritic cells involving of Jak2/STAT3 pathway, and there may be different mechanisms by which adriamycin-resistant BCC restrains DC function in antitumor immune response an IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma Pancreatic cancer stem cells jhave a role in developing chemoresistance toward gemcitabine treatment through the Nox/ROS/NF-kappaB/STAT3 signaling pathway. Results show that STAT3 expression is under the regulation of MiR-125b which targets its 3'UTR. study provided evidence that rs1053004 T > C in 3'UTR of STAT3 may decrease the risk of pancreatic cancer through up-regulation of the gene expression. STAT3 activation downregulates the ZO-1 and occludin levels and increases the endothelial permeability through the induction of VEGF production in retinal endothelial cells. High STAT3 expression is associated with glioblastomas. High STAT3 expression is associated with Hepatocellular Carcinoma. CD36/STAT3 SNPs linked to cardiovascular disease may modulate the effects of different diets on biochemical and inflammatory markers among these subjects. High STAT3 expression is associated with invasiveness of pancreatic intraepithelial neoplasia and cancer. High STAT3 expression is associated with lung cancer. total serum IgE concentration is an inexpensive and robust tool for determining which patients with multiple early-onset autoimmunity are likely to have a STAT3 GoF mutation STAT3 role in in promoting intestinal epithelial cells migration IL-27 stimulation activated STAT1 and STAT3 in HeLa and T98G cells, suggesting that IL-27 engages the STAT1/3 pathway, which then leads to the upregulation of IL-6, IP-10, and MIG U/G SNP rs111904020 in 3'UTR of STAT3 regulated by miR-214 promotes hepatocellular carcinoma development. Multilayer OMIC data analysis uncovered methylation hallmarks in genetically defined Medullary thyroid carcinoma (MTC) and revealed JAK/Stat signaling effector STAT3 as a potential therapeutic target for the treatment of RET(M918T) MTCs Expression of LINC00520 is regulated by oncogenic Src, PIK3CA and STAT3, and may contribute to the molecular etiology of breast cancer. The findings support a role for STAT3 and HIF-1A in the regulation of LL-37 expression. These results suggested that STAT3 activation represents a potential target in nasal Nasal-type natural killer/T-cell lymphoma(NKTCL). WP1066 may be a promising agent in antitumor therapy against nasal NKTCL. lipopolysaccharides induces STAT3 activation in macrophages. p-STAT3 may be a useful prognostic factor for undifferentiated pleomorphic sarcoma (UPS). IL-6 down-regulation and decreased IL-6 protein level in prostate cancer PC3 cells by gallic acid resulted in diminishing of pSTAT3, pERK1/2, and pAKT signaling proteins which lead to the reduction of the cell survival, proliferation, and invasion in [...] RNA and protein expressions of NF-kappaB and STAT3 increased significantly in thyroid carcinoma tissues. Significantly suppresses the p-STAT3 expression and its downstream genes including CCL2 and Bcl2. A sustained exposure to IFN-gamma in human mesenchymal stem cells led to inhibition of STAT3 activity. In patients undergoing colorectal cancer resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Upregulation of tumor STAT3 may be an important mechanism whereby the tumor deregulates local and syste [...] Primary open angle glaucoma in type 2 diabetes: Implications of the IL-10/STAT3-mediated anti-inflammatory response Acquired lapatinib-resistant HER2-positive breast cancer cells had elevated IL-6, and that elevated IL-6 maintained the stemness population and property within these resistant cells through the activation of STAT3. mechanical load upregulates expression of Runx2 gene via potentiation of PC1-JAK2/STAT3 signaling axis, culminating to possibly control osteoblastic differentiation and ultimately bone formation. HSP27 was found to be regulator of translation initiation and STAT3 level. Therefore, it suggests that HSP27 is a key protein during placental development and trophoblast cell differentiation. Calcitriol treatment of the TL-1 cell line (model of T-LGLL) led to decreased phospho-Y701 STAT1 and phospho-Y705 STAT3 and increased vitamin D receptor (VDR) levels. results demonstrated that OEA exerts anti-inflammatory effects by enhancing PPARalpha signaling, inhibiting the TLR4-mediated NF-kappaB signaling pathway, and interfering with the ERK1/2-dependent signaling cascade (TLR4/ERK1/2/AP-1/STAT3), which sug [...] Human prostate tumors with IL-6 elevation and loss of ESE3/EHF were associated with STAT3 activation and displayed upregulation of genes related to cell adhesion, cancer stem-like and metastatic spread. Elucidation of GM-CSF signaling demonstrates that the cytokine causes the activation of mTOR kinase, leading to the phosphorylation and activation of STAT3, which, in turn, is responsible for OCTN2 transcription. Hepatitis B virus (HBV) suppressed miR-204 expression via activating a host transcription factor STAT3. No significant relationship between IL-6 and STAT3 expression. Extracellular glutamine activates transcription factor signal transducer and activator of transcription 3 (STAT3), which is necessary and sufficient to mediate the proliferative effects of glutamine on glycolytic and oxidative cancer cells. this study demonstrates that STAT3 is activated in pancreatic cancer stem-like cells and that constitutively activated STAT3 in these cells enhances proliferation and survival. Targeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC. The Foxp3 expressed in CD4(+)CD25(+)Foxp3(+)Tregs was correlated with the histological grade, lymph node metastasis and TNM stage of CRC .The IL-10 expression was correlated with the histological grade and TNM stage. The Stat3 expression was correlat [...] this study shows that reciprocal regulation of miR-124 and STAT-3 in myeloid-derived suppressor cells promotes Treg cell development, thus uncovering a novel mechanism for the expansion of myeloid-derived suppressor cells and Treg cells during hepati [...] Concurrent STAT3, DNMT3A, and TET2 mutations in T-LGL leukemia with molecularly distinct clonal hematopoiesis of indeterminate potential we hypothesize that FOXM1 regulates radioresistance via STAT3 in GBM cells. We also, show GBM patients with high FOXM1 expression have poor prognosis. Results show that high ph-STAT1 and ph-STAT3 tumor cell expression were associated with increased ER and PR, reduced tumor grade and necrosis. STAT1 and STAT3 expression appeared to be an important determinant of favorable outcome in patients with in [...] our findings revealed a previously unrecognized regulation of STAT3 activation in tumor cells by cancer/testis antigen MAGEC2, and provided a molecular mechanism for the oncogenic activity of MAGEC2 in cancer cells. LMP2A signaling results in STAT3 phosphorylation in B cells through a PI3K/BTK-dependent pathway. Results show that STAT3 activation in FaDu hypopharyngeal cancer cell line was responsible for macrophage AEG-1-induced increased MMP-9 expression and invasion ability of FaDu cells. Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional chemotherapy for patients with high-risk neuroblastoma the effect of STAT3 mutations on protein stability, is reported. These findings support a role for CXCL1 and IL-8 in cystic fibrosis lung disease severity and identify STAT3 as a modulating pathway. the expression of HSP110 in colon cancer contributes to STAT3-dependent tumor growth miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. miR-124, IL-6R and STAT3 are involved in the process of sulforaphane-improved CDDP chemotherapy efficacy by targeting cancer stem cell-like properties MAPK signaling may control the expression of PD-L1 and several genes related to enhanced cell motility. Our findings suggest that MAPK, along with STAT3, is important for determining PD-L1 expression, which could be useful for targeted therapies agai [...] STAT3 rs3816769 with the (C) allele and (CC) genotype was found to be protective for CD while the (T) allele and (TT) genotype increased the risk of late onset and stricturing the disease. rs957970 was found to be associated with only CD. rs8074524 w [...] mRNA expression levels of 1279 genes were found to be associated with phosphorylated STAT3(705) expression. this study shows that sHLA-G causes a functional and quantitative induction of myeloid-derived suppressor cells through engagement of ILT4 and activation of STAT3 Long noncoding RNA antisense-IL6 induces IL6 expression and activates the IL6/STAT3 pathway. Results suggest that activated STAT3 regulates active beta-catenin protein levels via stabilization of SIAH-1 and the subsequent ubiquitin-dependent proteasomal degradation of beta-catenin in HEK293T cells. High STAT3 expression is associated with pancreatic cancer. CYT-Rx20 significantly reduced tumor growth of the implanted esophageal cancer cells accompanied by decreased Ki-67, phospho-AKT, and phospho-STAT3 expression. Insights into a molecular mechanism by which MEK5 transcriptionally upregulated by Stat3 augments breast cancer cell EMT, which subsequently enhances cancer cell invasion and metastasis. This finding may suggest that Stat3 and MEK5/Erk5 pathways coul [...] a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence. Interaction of stattic, a STAT3 inhibitor with human serum albumin: spectroscopic and computational study. overexpression of KIAA0247 is able to inhibit phosphorylation of AKT and Stat3 in glioma cells, resulting in inactivation of the AKT and Stat3 signaling pathways, this ultimately decreases the expression of PCNA, CyclinD1, Bcl2 and VEGF. STAT3 inhibition by polyphenols is a novel therapeutic strategy for melanoma. (Review) the data indicates that the potential application of cardamonin as a STAT3 blocker can mitigate both the growth and survival of prostate cancer cells Cancer-associated fibroblasts treated with cisplatin facilitate chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway. Blimp1, Foxp1 and pStat3 are expressed in extranodal diffuse large B-cell lymphomas findings suggest that EZH2 possesses anti-apoptotic activity in gastric tumorigenesis following STAT3 activation As a result of Tumour-associated macrophages (TAMs)-induced activation of the STAT3 pathway, murine 5T33MM cells are sensitized to AZD1480 treatment. miR-124 could directly target the 3'-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. inhibition of any internalization mechanism impaired activation of STAT3 but not of other downstream effectors of PDGFRbeta. These findings also identify STAT3 as a therapeutic target against viral infection and highlight it as an essential pathway component for endogenous and therapeutic IFN-alpha responsiveness. Moderate to strong pSTAT3 expression in >/=10% of cells was found to be a negative prognostic factor for disease-specific overall survival among primary malignant peripheral nerve sheath tumours, suggesting a role of pSTAT3 in the progression of these tumours miR-340 suppressed HCC cell proliferation and invasion by regulating the JAK1/STAT3 pathway inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma constitutively acetylated STAT3 localizes to mitochondria, where it maintains the mitochondrial membrane potential and ATP synthesis in an active state Data indicate that phosphorylation of Janus kinase 3 (JAK3) and STAT3 transcription factor (STAT3) was inhibited by latent membrane protein 1 (LMP1)-IgG. Propofol could enhance the anti-tumor effect of cisplatin through EGFR/JAK2/STAT3 pathway. Metformin targets STAT3/NFkappaB signaling to inhibit proliferation/invasiveness of cholangiocarcinoma cells. Suggest that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with triple negative breast cancer. Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation to prevent cell proliferation and migration. STAT3 overexpression promotes the invasion, metastasis and proliferation of intrahepatic cholangiocarcinoma carcinoma cells and predicts poor overall survival and disease-free survival. The results revealed that although the expression levels of SOCS1, SOCS3 and, in particular, pSHP2, tend to decrease in the four types of astrocytomas, PIAS3 downregulation is more negatively correlated with STAT3 activation in the stepwise progress [...] SHP2, SOCS3 and PIAS3 levels are reduced in medulloblastomas in vivo and in vitro, of which PIAS3 downregulation is more reversely correlated with STAT3 activation. In resveratrol-suppressed medulloblastoma cells with STAT3 downregulation and decreas [...] Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in tumor extracellular vesicle (EV)-educated mesenchymal stem cells -treated mice our results indicated that nifuroxazide could effectively inhibit tumor metastasis by mediating Stat3 pathway and it might have a therapeutic potential for the treatment of Colorectal carcinoma (CRC) . Data show that the IL-6/STAT3/TWIST signaling pathway was activated during ionizing radiation (IR)-induced epithelial-mesenchymal transition (EMT), and that STAT3 inhibition or Twist depletion reversed the EMT process and attenuated radioresistance. High phosphorylated stat3 expression is associated with gallbladder cancer. Data show that succinate upregulates vascular endothelial growth factor (VEGF) expression by activation of signal transducer and activator of transcription 3 (STAT3) and extracellular regulated kinase (ERK)1/2 via its receptor G-protein coupled recep [...] We postulate that SIRT1 and STAT3 are potential early diagnostic and prognostic markers of gastric cancer In summary, this study has shown that LIF is implicated in the HG-mediated inhibition of osteoblast differentiation, via promoting STAT3/SOCS3 signaling. This study may provide insights into the signal pathway of HG-induced bone loss or delayed injur [...] By deacetylating and deacetyliminating Stat3 on multiple acetyl-lysine sites in nuclei, Loxl3 regulates Stat3 dimerization and transcriptional activity. CD4+ T cell differentiation in inflammatory responses is regulated by the Loxl3-Stat3 signaling pathway Results provide evidence that STAT3 expression is regulated by Fbw7 with interacts with it and pStat3(Tyr705) to regulate their ubiquitylation and degradation. A mutation in STAT3, a heterozygous C to T transition in exon 10 of the STAT3 gene at position 988 of the coding DNA sequence, results in neonatal diabetes via reduced insulin synthesis. Shp2 (Src-homology 2 domain-containing phosphatase 2) functions as a negative regulator for STAT3 transcription factor (Stat3) activation in esophageal squamous cell cancer (ESCC). Icaritin significantly inhibited the expression of phospho-signal transducer and activator of transcription 3 (p-STAT3) in a dose- and time-dependent manner. STAT3 signaling induced by therapeutic stress in EGFR-driven triple-negative breast cancers might override normal epithelial homeostatic mechanisms and provide a survival advantage for tumor cells before they leave the primary tumor and spread to dis [...] STAT3 signaling mediates tumor resistance to EGFR targeted therapeutics. (Review) p65 expression correlates with elevated total cellular levels of STAT3 and STAT1 and supports activation of these transcription factors. STAT3 is a critical mediator of tumorigenesis, tumor progression, and suppression of anti-tumor immunity in glioblastoma multiforme. (Review) DNMT1 up-regulation induced by IL-6/STAT3 signaling was indispensable for IL-6-mediated hepaCAM loss in renal cell carcinoma (RCC) cell lines ACHN and 769-P, while DNMT3b up-regulation was crucial for hepaCAM loss in A498. results suggest that methanethiosulfonate moiety can be considered a useful scaffold in the preparation of new direct STAT3 inhibitors TRIM8 activates STAT3 by suppressing the expression of PIAS3, an inhibitor of STAT3, most likely through E3-mediated ubiquitination and proteasomal degradation. Upregulation of STAT3 is associated with breast cancer. Suppression of GPRC5a results in decreased cell growth, proliferation and migration in pancreatic cancer cell lines via a STAT3 modulated pathway, independent from ERK activation signal transducer and activator of transcription (Stat)3 represses Smad3 in synergy with the potent negative regulators of TGF-beta signaling, c-Ski and SnoN, whereby renders gefitinib-sensitive HCC827 cells resistant These findings expand the known mechanisms of MIR506-mediated tumor suppression to activation of autophagy-related cell death and suggest a strategy for using MIR506 as an anti-STAT3 approach to Pancreatic ductal adenocarcinoma treatment. Data show that cisplatin suppresses cervical cancer cell movement and angiogenesis via regulating miR-29b/STAT3 axis. STAT3 activation promotes ERBIN expression and negatively regulates TGF-beta activity by the formation of a STAT3-ERBIN-SMAD2/3 complex. data demonstrated that Tipalpha may accelerate tumor aggressiveness in gastric cancer by promoting EMT through activation of IL-6/STAT3 pathway These findings indicate that viral replication and inflammation are linked through a common IFNgamma-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. The interaction between ganlyrin and SHP-1 leads to inhibition of STAT3 activation and to enhancement of TNF-alpha and IL-17 in inflammatory cells. STAT3 S-nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. Results indicate a pathway via which microRNA miR-17-5p inhibits STAT3 and increases p53 expression to promote apoptosis in breast cancer cells. STAT3 and ATG12 are targets of miR-454-3p. luteolin inhibited STAT3 activation through disrupting the binding of HSP-90 to STAT3, which promoted its interaction to SHP-1. Our findings suggested the hypothesis that the overexpression of lnc-DC acts through the p-STAT3 pathway to induce the over-maturation of decidual DCs in preeclampsia patients. Data suggest that C-terminal truncated hepatitis B virus X protein (HBx-DeltaC1) enhances liver cancer stem cell (CSC) properties through Stat3/Nanog cascade, and insight for the therapeutic intervention for hepatitis B virus (HBV)-related hepatocell [...] findings reveal a new signaling axis downstream of the cytosolic DNA pathway and suggest potential interactions between innate immune responses and STAT3-driven oncogenic pathways As targets of oncogenes with intrinsic tyrosine kinase activity, STAT3 and STAT5 become constitutively active in hematologic neoplasms and solid tumors, promoting cell proliferation and survival and modulating redox homeostasis via regulation xCT exp [...] Phosphorylation of STAT3 was decreased in NRDC-depleted Huh-7 spheroids. Findings define a STAT3-miR-92a-DKK1 pathway in the generation of cancer stem-like cells in ovarian tumors. Mitochondria-targeted esculetin has anti-atherosclerotic effects by inhibiting PAI-1 levels by modulating miR-19b and -30c expression and affecting SIRT3- and STAT3-mediated signaling pathways. IRE1alpha-XBP1 pathway regulates Mel-RMu cell proliferation and progression by activating IL-6/STAT3 signaling. Infection with bacterial AvrA-expressing Salmonella activates the STAT3 pathway, which induces the beta-catenin signals and enhances colonic tumorigenesis. (Review) IFITM2 promotes gastric cancer growth and metastasis via IGF1/IGF1R/STAT3 signaling pathway. miR-145 suppressed STAT3 phosphorylation at Tyr705 and increased foxo1 promoter transcriptional activity in T24 cells, but not in T24T cells, suggesting a role of STAT3 in the divergent responses to miR-145. simvastatin also increased p21 and p27 expression in tumor sections by reducing Skp2 expression and inducing AMPK activation and STAT3 suppression in the same tumor tissues. Overexpression of REP1 in BEAS-2B cells enhanced cell growth and anchorage-independent colony formation with little increase in EGFR level and STAT3 activation. these data document the S-nitrosylation mediated inhibition of multiple myeloma (MM) cell proliferation and cell survival via inhibition of STAT3 and NF-kappaB pathways and its efficacy in animal model of MM STAT-1, STAT-3, and STAT-5b expression was also enhanced after IL-21 treatment, with STAT-3 being the most significantly enhanced Low-dose radiation decreases tumor progression via the inhibition of the JAK1/STAT3 signaling axis in breast cancer cell lines and in a mouse xenograft model. Kidney biopsies from patients with IgA nephropathy and diabetic nephropathy exhibited substantial activation of p53 and STAT3, decreased expression of SOCS7, and increase in profibrotic proteins and miR-199a-3p. Interferon-alpha-enhanced IL-10 expression in human CD4 T cells is regulated by STAT3, STAT2, and BATF transcription factors. lithocholic acid activated Erk1/2 and in turn, suppressed STAT3 phosphorylation to induce IL-8 expression in HCT116 cells, thus stimulating endothelial cell proliferation and tube like formation. Editing in the STAT3 intron is performed by ADAR1 and affects STAT3 alternative splicing. RNA editing is one of the molecular mechanisms regulating the expression of STAT3beta. The indirect co-culture of SCLC cells and macrophages induced STAT3 activation in both cell types, and macrophage-derived culture supernatant (CS) significantly activated STAT3 in SCLC cells. results suggested that crocin is a novel inhibitor of STAT3 activation pathway and thus may have potential in prevention and treatment of human multiple myeloma. The increased activity was reduced by STAT3 silencing. dehydrocostus lactone significantly inhibits the phosphorylation expression of Bcr/Abl, STAT5, JAK2, and STAT3 and downstream molecules including p-CrkL, Mcl-1, Bcl-XL, and Bcl-2 proteins in K562 cells. miR-1181 may be involved in pancreatic cancer cell invasion and proliferation by targeting STAT3 miR-21 overexpression promotes cardiac fibrosis via STAT3 signaling pathway by decrease CADM1 expression, indicating miR-21 as an important signaling molecule for cardiac fibrotic remodeling and atrial fibrillation. Data show that FZU-03,010 suppresses the signal transducer and activator of transcription 3 (STAT3) activation more potently than ursolic acid (UA) in renal carcinoma 786-0 and triple negative breast cancer (TNBC) HCC1806 cells. this is the first study to show that PD-L1 gene amplification is not detected, but PD-L1 protein is commonly expressed in ALK- ALCL tumors. More importantly, PD-L1 expression is transcriptionally regulated by STAT3 and MYC in ALK- ALCL, thus providin [...] Fzd2 expression induced EMT and enhanced cell migration and invasiveness, and it might be a novel predictor of HCC recurrence. Furthermore, Stat3 might be controlled by both the Wnt5/Fzd2 and IL-6/Jak2 signaling pathways and play an important role in EMT. splicing factor 3b subunit 4 was found to inhibit the activity of signal transducer and activator of transcription 3 signaling via downregulating the phosphorylation of signal transducer and activator of transcription 3 on a tyrosine residue at position 705. we demonstrate that the drugs dephosphorylated STAT3, a major regulator of mesenchymal and neural stem cell markers implicating the role of STAT3 in the inhibitory action of these drugs. The findings demonstrate the potential of mTOR inhibitors as "s [...] We concluded that hnRNPA2B1 promotes the tumorigenic potential of breast cancer cells, MCF-7 and MDA-MB-231, through the extracellular-signal-regulated kinase 1/2 or signal transducer and activator of transcription 3 pathway, which may serve as a tar [...] Binding of signal transducer and activator of transcription 3 (STAT3) to cyclophilin D (CypD) was important for reducing mitochondrial reactive oxygen species (ROS) production after oxidative stress. STAT3 is required for the survival of anaplastic large cell lymphoma.Stat3 mutations in anaplastic large cell lymphoma. These results demonstrated that BrMC inhibits the stemness of LCSLCs originated from SMMC-7721 cell line by inhibiting STAT3/Twist signal axis. These findings show for the first time that DSF suppresses stem-like properties in TNBC by targeting the STAT3 signaling pathway. Study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhan [...] There was an obvious reduction in the level of the transcription factor pSTAT3 in patients with Non-allergic Asthma and an increase in that in patients with Allergic Asthma. STAT3 polymorphism is a novel risk factor for sunitinib-induced stomatitis in Japanese patients with metastatic renal cell carcinoma. results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells High STAT3 expression is associated with cisplatin resistance in epithelial ovarian cancer. G7mAb enhanced the antitumor effect of cetuximab by attenuating phosphorylation of Src/STAT3. Collectively, our results demonstrate that the STAT3(K392R) mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression. The activation of NF-kappaB and STAT3 signalling-dependent pro-inflammatory cytokine expression. Studied interactions of polypyrimidine tract-binding protein (PTBP1), pyruvate kinase M2 (PKM2), and STAT3 (signal transducer and activator of transcription 3) in oncogenesis of anaplastic large cell lymphoma (ALCL). Results show that in ALCL cells, [...] rs744166GG in STAT3 and rs7574865TT in STAT4 had higher frequencies in the case than the control group, suggesting these 2 genotypes increase the susceptibility to psoriasis ( p < 0.05). Our finding supports that STAT3 was the potential treated target for breast cancer therapy, whereas STAT5A/5B/6 were potential prognostic markers for better survival of BC, providing more accurate prognosis. Stromal ADSCs promote osteosarcoma progression by increasing STAT3 signalling-mediated MMP2/9 expression. High STAT3 expression is associated with resistance to sorafeinib in liver cancer. Data suggest PML (promyelocytic leukemia protein) positively regulates STAT1 and STAT2 isgylation, a ubiquitination-like protein modification; PML exhibits potent angiostatic activity, doing so in part by forming a positive feedforward loop with STAT [...] The findings support STAT3 as a positive mediator of EGF-induced apoptosis in MDA-MB-468 cells. Taken together, we found that silibinin inhibits the Jak2/STAT3/MMP2 signaling pathway, and inhibits the proliferation, migration, and invasion of triple-negative breast cancer cells. hypoxia-induced IL-6 production in endometriotic lesions is mediated via downregulation of DUSP2, which causes aberrant activation of STAT3 signaling pathway and helps the endometriotic cells survive under the ectopic environment Results suggest that mTOR-STAT3-HK2 pathway is involved in the glycolysis of HCC cells and STAT3 may regulate HCC glycolysis through HK2 pathway. The results suggested that HGF may inhibit TEMT by inhibiting AngII through the JAK2/STAT3 signaling pathway in HK2 cells and HGF may prevent apoptosis induced by AngII. The present study provides a basis for understanding the mechanisms involved in [...] Our study showed that the expressions of HER2, STAT3, and SOCS3 are associated with the progression of ovarian cancer (OC), and higher expressions of HER2 and STAT3 and lower expression of SOCS3 predict poor prognosis of OC. These findings suggest a novel STAT3 to NCK1 to PAK1/ERK signaling mechanism that is potentially critical for colorectal cancer metastasis and angiogenesis. Auto-antibody production in response to plasma cell-niche cytokines that are usually at high levels in systemic lupus erythematosus patients is dependent on JAK/STAT-3 activation we demonstrated a mechanistic cascade of TMPRSS4 up-regulating STAT3 activation and subsequent TWIST1 expression, leading to prostate cancer migration. TPD52 activates STAT3 through ascertaining a cross talk between the nuclear factor-kappaB and the STAT3 signaling systems. Collectively, these results reveal mechanism by which TPD52 is associated with prostate cancer progression and highlight the ap [...] Results show that STAT3 is activated after binding to Anxa2-Tyr23 phosphorylation which promote the progression of breast cancer. Findings suggest that activated STAT3 (phosphorylated STAT3) may play a role in adult-onset Still's disease and that the STAT3-activating pathway may be a therapeutic target. The results suggest that SH3GL2 suppresses migration and invasion behaviors of glioma cells through negatively regulating STAT3/MMP2 signaling. a transcription-independent mechanism for Stat3-mediated centrosome clustering that involves Stathmin, a Stat3 interactor involved in microtubule depolymerization, and the mitotic kinase PLK1, is reported. our data elucidate that knockdown of HOXD-AS1 dramatically suppresses gastric cancer cell growth by inactivating the Janus kinase 2/signal transducer and activator of transcription 3 pathway in vitro and in vivo, contributing to a better understandin [...] Activated STAT3 upregulates the expression of GPx1 and SOD2, which reduce the intracellular ROS levels in Burkitt lymphoma. Data obtained showed different STAT3 PTMs profiles among the analyzed tumor grades which correlate with differences in the amount and distribution of specific STAT3 interactors as well as the expression of STAT3 target genes. These results highlight [...] Peritoneal membrane dysfunction in long-term peritoneal dialysis patients may result from IL-6 promotion of epithelial-to-mesenchymal transition of human peritoneal mesothelial cells possibly through the JAK2/STAT3 signaling pathway. The inhibitory action of cryptotanshinone is largely attributed to the inhibition of STAT3 Tyr705 phosphorylation with a novel mechanism of upregulating the tyrosine phosphatase activity of SHP-2 protein. Together, these data demonstrated that STAT3 was beneficial to bone fracture healing, possibly by enhancing Treg-mediated suppression of counteracting inflammations, and suggested that STAT3 could be used as a prognostic marker to identify otherwise [...] We also confirmed that the overexpression of miR-1299 can not only downregulate the STAT3 pathway, but also inhibited colon cancer cell growth. Our findings could provide new insights into the molecular therapeutic of colon cancer. miR-495 can directly target 3'-UTR of STAT-3 mRNA and thereby decrease the expression of STAT-3 in MCF-7 and HCC1973 cells by Targetscan and Dual-luciferase assay. We further analyzed miR-495 promoter methylation by sodium bisulfite sequencing method [...] results suggest that W2 suppresses cancer cell migration and invasion by inhibiting FAK/STAT3 signaling and STAT3 translocation to the nucleus in monomorphic malignant human glioma cells. miR-93-5p regulates myocardin-like 1 and STAT3 to affect epithelial-mesenchymal transition controlling breast cancer cell migration High STAT3 expression is associated with glioma. Overexpression of CXCR4 facilitated tumor growth and angiogenesis in SGC7901 xenograft tumors, which was associated with increased levels of phospho-STAT3. CXCR4 contributes to tumor angiogenesis in gastric cancer by inducing STAT3-dependent VEGF expression. Ellipticine treatment led to a significant inhibition of STAT3-mediated transcriptional activity in RA-FLSs. STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. Ascochlorin significantly decreased phosphorylation of JAK2/STAT3, cancer cell migration and nuclear translocation of STAT3. Study shows that vascular endothelial growth factor A stimulates STAT3 activity via nitrosylation of myocardin to regulate the expression of vascular smooth muscle cell differentiation markers. that loss of RIP4 enhances STAT3 signaling in lung cancer cells Study found that inhibition of either GSK3beta or STAT3 alone resulted in a significant decrease in esophageal squamous cell carcinoma (ESCC) cell viability and migration both in vitro and in vivo, indicating that dysregulation of either GSK3beta or [...] STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction. These findings revealed that miR-138 might promote angiogenesis of human cytomegalovirus (HCMV)-infected HUVECs by activating the SIRT1-mediated p-STAT3 pathway, and this could provide novel insights into HCMV-induced angiogenesis Two dominant gain-of-function mutations of STAT3 were identified in children with autoimmune lymphoproliferative syndrome-like disease. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cance [...] This study provides insights on the role of mSTAT3 in cancer cells. Mast cells deplete stemness features of glioma cells and induce differentiation. Mast cells exert their effect via inactivation of STAT3 through GSK3 beta downregulation. BRM could activate JAK2/STAT3 pathway to promote pancreatic cancer growth and chemoresistance. Human Growth Hormone Inhibits CLAUDIN-1 Expression Through Activation of Signal Transducer and Activator of Transcription 3 (STAT3). this study demonstrates that the hepatocarcinogenic effect of N-nitrosodiethylamine can be abrogated by gallic acid supplementation owing to its affinity to regulate signal transducer and activator of transcription 3 signaling pathway through its out [...] In this review, we summarize the recent literature and concepts on non-coding RNAs that are regulated by/regulate nuclear factor kappa B and signal transducer and activator of transcription 3 in esophageal cancer progression. These results demonstrate that targeting NFkappaB/PDL1/STAT3/DNMT1 axis is a new therapeutic strategy for preventing or overcoming the acquired resistance to sorafenib in hepatocellular carcinoma (HCC)patients Taken together, mir-125a-5p inhibited the proliferation and invasion of lung cancer cells and facilitated lung cancer cell apoptosis through suppressing STAT3. Enhancing the expression of miR-125a-5p is expected to benefit the therapy for the patient [...] we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in ovarian clear cell carcinoma (OCCC) cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standar [...] MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers. Low STAT3 expression is associated with gastric cancer. Inhibition of drug resistance by apigenin is related to the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway The promoter of FOXL2 was successfully cloned and registered in Gen Bank, and a dual luciferase reporter (DLR) analysis demonstrated that the luciferase activity was significantly induced by the promoter of FOXL2. Subsequently, bioinformatics analysi [...] High STAT3 expression is associated with hepatocellular carcinoma. This study demonstrates that obesity-associated inflammation and metabolic disturbances depend on interleukin-6/Stat3-dependent formation of a distinct natural killer population, which may provide a target for the treatment of obesity, metaflammation [...] Findings show the coexistence of two post-translationally modified STAT3alpha isoforms with distinct functions and define a new role for STAT3 as a molecular adaptor that functions independently of its canonical transcriptional activity during human [...] These results suggest that it may be possible for Evista to emerge as a chemoprevention agent for breast cancer and other cancers such as colon cancer or multiple myeoloma by targeting IL-6/STAT3 signaling. Elevated S1PR1 expression and STAT3 activation are also observed in human NB cells with acquired resistance to etoposide. We show in vitro and in human NB xenograft models that treatment with FTY720, an FDA-approved drug and antagonist of S1PR1, dram [...] High STAT3 expression is associated with B-cell lymphoma. MiR-98 as a anticarcinogenic functions through targeting STAT3. The results suggested the possible participation of STAT3 instead of ERK in the GPR110 signaling pathways and progression of glioma. IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner We demonstrate that leptin stimulates the phosphorylation of STAT3 in LEPRb-transfected non-CSCs compared with non-transfected non-CSCs. The increased expression of LEPRb and STAT3 activation recapitulated the phosphorylation status of STAT3 in CSCs. [...] the data of the present study indicate that IL6R/STAT3/miR34a possesses a protective role in patients with neonatal lung injury. HSP90 is an upstream regulator of the ACK1-dependent phosphorylation of STAT1 and STAT3. Data show myoferlin depletion did not affect STAT3 transcription factor (STAT3) phosphorylation, but completely blocked STAT3 translocation to nucleus. Findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI. High STAT3 expression is associated with recurrence in Glioma. Our findings revealed that B7-H3 affect ovarian cancer progression through the Jak2/Stat3 pathway, indicating that B7-H3 has the potential to be a useful prognostic marker. The investigation demonstrated that the serum levels of FGF23 and the phosphorylation levels of JAK2, STAT1, and STAT3 were up-regulated in the ovariectomy (OVX) + NVP-BGJ398 group while were down-regulated in the OVX + Anti-FGF23 group than that in [...] Studied role of RAB3C overexpression in tumor metastasis and poor prognosis of colorectal cancer. Found RAB3c is associated with modulating exocytosis of IL-6 in cancer cells, leading to activation of the IL6-JAK2-STAT3 pathway. This analysis indicated that corilagin is mainly involved in the glycolysis pathway. Seahorse XF96 extracellular acidification rate analysis confirmed that corilagin inhibited glycolysis by downregulation of CD44 and STAT3 we showed that DMKN loss of function in Patu-8988 and PANC-1 pancreatic cancer cell lines resulted in reduced phosphorylation of STAT3.these data suggested that DMKN could be a potential prognostic biomarker and therapeutic target in pancreatic cancer. p-STAT3 overexpression has significant correlation with poorer overall survival of lung cancer patients, as well as with more advanced TNM stages and lymph node metastasis. [meta-analysis] The PKM2 may promote hepatic IR via STAT3 pathway and would provide a new insight into dissecting the molecular pathogenesis of hepatic insulin resistance. These findings suggest that the STAT3 pathway may be implicated in a new mechanism for the pathogenesis of several GI disorders Mutation inactivating STAT3 gene is associated with Breast Cancer Metastasis. Studied upregulation of long noncoding RNA (lncRNA) HOXD-AS1 in liver cancer. Found STAT3 could combine to the promoter of HOXD-AS1 and activate the transcription of HOXD-AS1, and further found evidence that lncRNA HOXDAS1 shared miRNA response eleme [...] Data indicate that IL-6 induces M2 macrophage differentiation (IL-10(high)TGF-beta(high)IL-12 p35(low) ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration. Studied the tumor suppressive role and antiproliferative effect of MicroRNA-218 in lung cancer cells through targeting of IL-6/STAT3 pathway. High STAT3 expression is associated with peritoneal metastasis in gastric cancer. Our results revealed that using WP1066 to inhibit the STAT3 signaling pathway suppressed the viability and invasiveness of bladder cancer cells effectively and could be a novel therapeutic strategy against bladder cancer. The irradiated cells, their secretome, and the nonirradiated recipient cells showed similar inflammatory response, characterized by induction of interferon type I-related proteins and activation of the STAT3 pathway. These data indicate that irradiat [...] These results suggest that the phosphorylation of STAT3 regulates MMP-9 production in ovarian cancer, which might be responsible for its invasiveness and metastasis. In this review, we focus on the reciprocal regulation and roles of microRNAs and signal transducer and activator of transcription 3 in cancer, as well as describe current research progress on this relationship. A better understanding of this relation [...] Studied the role of ZEB1-AS1, and it's association with IL-11, in promoting STAT3 activation in B-lymphoblastic leukemia. Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-beta signaling. Amorfrutin A is a potent inhibitor of STAT3. Review of the role of STAT1 and STAT3 gain-of-function mutations in primary immunodeficiency/immunodysregulation disorders. In Ishikawa human endometrial adenocarcinoma cell line MIG-6 negatively regulates the phosphorylation of STAT3 via direct protein interaction with STAT3. GRIM-19 suppresses the proliferation and invasion of cutaneous squamous cell carcinoma cells associated with downregulation of STAT3 signaling. STAT3 mediates anoikis resistance, with enhanced cell migration and invasion of NPC cells, and that activation of STAT3 may increase metastatic capacity, indicating the crucial role of STAT3 in conferring anoikis resistance and enhanced invasive prop [...] Which was also linked to suppression of STAT3 phosphorylation. The concentration and mRNA level of cytokines was altered by the regulation of STAT3 expression and the concentration and mRNA expression level of cytokines was positively correlated with STAT3 activation. STAT3 was correlated with cytokine expressio [...] PAI-1 was identified as the target gene of miR-34a and activated the Stat3 signaling pathway to promote epithelial-mesenchymal transition in non-small cell lung cancer cells. MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling. 6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiated the inhibitory effect of IFN-alpha on hepatocellular carcinoma cell proliferation through activation of the JAK/STAT signaling pathway by inhibiting SOCS3 expression. The binding of IL-22 to IL-22 receptor induces STAT3 activation. We investigated the effect of IL-22 on the expression in airway epithelial cells in vitro after the stimulation with an analog of viral double-stranded RNA. Treatment of cells with STAT [...] STAT1 Gain-of-Function and Dominant Negative STAT3 Mutations Impair IL-17 and IL-22 Immunity Associated with Chronic mucocutaneous candidiasis. STAT3 signaling is hyperactivated in systemic sclerosis in a TGFbeta-dependent manner TGR5 exhibits significantly higher expression in NSCLC tumor samples and facilitates the growth and metastasis of NSCLC by activating the JAK2/STAT3 signaling pathway. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardia [...] Stat3 ubiquitination-mediated degradation is regulated by La protein. It is a potential therapeutic targets for gastric adenocarcinoma. Astrocyte elevated gene-1 shows the ability to promote bladder cancer metastasis, which is causally linked to induction of signal transducer and activator of transcription 3 activation and epithelial-mesenchymal transition. Enterovirus 71 antagonizes the antiviral activity of host STAT3 and IL-6R with partial dependence on virus-induced miR-124. Results show that STAT3 deacetylation is under the regulation of HDAC7 which interacts directly with STAT3. AG490 can down-regulate expression of STAT3 and p-STAT3 protein in C666-1 cells, inhibit proliferation of nasopharyngeal carcinoma cells and promote apoptosis of nasopharyngeal carcinoma cells. reveals a new role of mitochondrial Stat3 in preventing ASK1/p38(MAPK)-mediated apoptosis. Positive cooperativity of Smad3 and STAT3 during epithelial-mesenchymal transition [Review]. Activated STAT3 is not the limiting factor for collagen enhancer activation in human lung fibroblasts. Yet, a certain threshold level of STAT3 activity is essential to support activation of the COL1A2 enhancer and TGFbeta signaling in fibroblasts. It [...] The expression level of the STAT3 gene did not differ between patients with systemic sclerosis and controls. STAT3 activation and MYC expression were critical for the proliferation and survival of Aggressive NK-cell Leukemia cells. CaP@LDL-mediated STAT3-decoy ODN delivery might be a promising new strategy for reversing TRAIL resistance in hepatocellular carcinoma therapy. a second tyrosine phosphorylation within the SH2 domain at position Y640, induced by Tyk2, negatively controls STAT3 activity. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting tumor growth In leukemia [Review]. Wdrug resistance through blocking p-STAT3/p65 and Bcl-2 activation. homeobox A5 and signal transducer and activator of transcription 3 were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in [...] Suggest a positive feedback mechanism via the STAT1/3 pathway sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFalpha-mediated senescence. High STAT3 expression is associated with doxorubicin-resistance in breast cancer. data indicates that Blcap is a novel Stat3 interaction partner and suggests a role for Blcap in the Stat3-mediated progression of precancerous lesions to invasive tumors of the bladder The expression of p-Ser-STAT3 can be a potential prognostic marker for cancer recurrence and survival in upper tract urothelial carcinoma , especially in advanced stage cases. the present study revealed that increased miR19b expression may delay unstable plaque progression in patients with UA by inhibiting EC proliferation, migration and angiogenesis via the suppression of STAT3 transcriptional activity our data indicate that phosphorylated -STAT3 is associated with an improved outcome in estrogen receptor-positive breast cancer. MALAT1can act as a competing endogenous lncRNA (ceRNA) to modulate miR-124/STAT3 in NSCLC. STAT3/NFIL3 axis-inhibited apoptosis is a novel mechanism of chemotherapy resistance in choriocarcinoma. With the suppression of STAT3/NFIL3 axis and apoptosis induction, RA is a potential agent or lead candidate for improving chemotherapy. somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia NEAT1 can act as a competing endogenous lncRNA (ceRNA) to regulated STAT3 by sponging miR-485 in HCC. Data indicate that signal transducer and activator of transcription 3 (STAT3) has emerged as a promising target in cancer immunotherapy [Review]. STAT3 expression is regulated by miR-26a in ambient particulate matter-bound metal-triggered lung cancer. a crucial role of STAT3 in regulating the epigenetic status of T cells in Latent autoimmune diabetes of adults (LADA). Data show that knockdown of STAT transcription factors STAT3 and/or STAT5 reduces DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) level. silencing of STAT3 reduced the proliferation and promoted the apoptosis of fibroblast-like synoviocytes. Recurrent STAT3-RARA fusion is associated with acute promyelocytic leukemia lacking t(15;17)(q22;q12)/PML-RARA. Constitutive activation of phosphatase SHP2 was found to negatively regulate IL-6 induced STAT3 phosphorylation in fibroblasts from severe asthmatics. SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer reveal that breast cancer stem cell (BCSC) in triple-negative breast cancer depend on the transcription regulator HN1L for the sustained activation of the LEPR-STAT3 pathway, which makes it a potentially important target for both prognosis and BCSC therapy. Study shows that STAT3 mRNA expression is upregulated in retinoblastoma (RB) tissues and negatively correlates with miR29a expression, and suggests that STAT3 is a potential target of miR29a. STAT3 augments epithelial-to-mesenchymal transition and cell migration in hepatocellular carcinoma. Overexpression of ALK4 suppressed glioma cell proliferation, migration and invasion through the inactivation of JAK/STAT3 signaling pathway. Mir-204 attenuates angiogenesis in lung adenocarcinoma via JAK2-STAT3 pathway. T-cell receptor gamma V-J rearrangement repertoire, and bone marrow biopsy morphology among the STAT3-mutation and wild-type groups other than significantly larger tumor burden in patients with STAT3 mutations Data suggest that targeting the ring finger 6 protein(RNF6)/protein-tyrosine phosphatase SHP-1 (SHP-1)/signal transducer and activator of transcription 3 (STAT3) axis provides a potential therapeutic option for RNF6-amplified tumors. Results suggest that STAT3 can regulate PTTG1 expression by binding to different site of PTTG1 promoter in various cancers and provide evidence the crucial role of STAT3 in development of androgen deprivation therapy resistance in castration-resistan [...] results illustrate that perhaps rs1053004 polymorphisms in the STAT3 gene participated in the progression of hepatitis B to hepatocellular carcinoma in Iranian people. Findings suggest that ibrutinib can inhibit miR-21 transcription by disrupting NF-kB and STAT3 binding to the miR-21 promoter. Among these genes, STAT3 and CDK2 were significantly associated with recurrence. Further study suggested that inhibition of CDK2 reduced invasion of Pca cell lines. The invasion ability was rescued after reintroduction of CDK2. These results indicate that BSNQ and OSNQ induce apoptosis in human hepatoma Hep3B cells via ROS-mediated p38/MAPK, Akt and STAT3 signaling pathways, suggesting that these 1,4-naphthoquinone derivatives may provide promising new anticancer agents to [...] RNASE4, STAT3, and miRNA-124 may have a regulatory association with the pathological mechanisms in Huntington's disease. Findings indicate the importance of the signal transducer and activator of transcription 3 (STAT3)/miR-200 family axis in early stage of disease. genetic association studies in population in southwest China: Data suggest that SNPs in STAT4 (rs7574865), IL23R (rs11209032), and STAT3 (rs744166) are associated with occurrence, severity, and immunosuppressive therapy outcomes of aplastic anemia in [...] These data show that activated p-STAT3 upregulates epithelial-to-mesenchymal transition-related proteins and promotes vasculogenic mimicry. The present results indicate that activation of the IL-6/STAT3 pathway contributes to the pathogenesis of thromboangiitis obliterans (TAO) by regulating cellular adhesion molecules and cytoskeleton of vascular endothelial cells. Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Findings outlined in the current study demonstrated that the inhibition of P16 decreased the growth and metastasis potential of BC cells by inhibiting IL-6/JAK2/STAT3 signaling. tyrphostin B42 induced the apoptosis of pancreatic cancer cells (PCCs) by regulating the expression of mitochondrialrelated genes. Therefore, these findings demonstrated that tyrphostin B42 attenuated trichostatin A resistance in PCCs by antagonizing [...] these results provide evidence that crocin has the potential for anticancer activity through inhibition of the IL-6/STAT3 signaling pathway, especially in liver cancer. The molecules inhibit STAT3 by interacting with its SH2 domain. A significant increase was observed in expression of STAT3 and lnc-DC genes but not SOCS1 in coronary artery disease \+ versus coronary artery disease- patients. Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor beta-chain (IL-2Rbeta) and a STAT3 [...] we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with curre [...] JAK2 and STAT3 are activated in Idiopathic pulmonary fibrosis Results show that gastric tumourigenesis as a consequence of hyperactive gp130/STAT3 signaling, is intrinsically linked with the development of submucosal tertiary lymphoid structures (TLSs) in gastric antrum tissue. Findings indicate that RFX1 functions downstream of STAT3 and phosphorylated STAT3 can inhibit RFX1 expression and suggest a unique role for RFX1 in Th17-related autoimmune diseases. icaritin reverses multidrug resistance in doxorubicin-resistant human osteosarcoma cells by blocking phosphorylation of signal transducer and activator of transcription 3 (STAT3). IFN-beta, by virtue of its activating the IDO/Kyn/AhR cascade and serine phosphorylation of STAT3, induces dormancy of melanoma tumor-repopulating cells In conclusion, p-STAT3 may participate in the progression of the early stage of colon cancer through the up-regulation of CD133, which in turn induces survivin expression. However, the regulatory mechanism of these molecules in tumor progression in v [...] we demonstrated that the STAT3 pathway was involved in miR-204/14-3-3zeta regulation of OS cell proliferation Data found that STAT3 activation and GLI1/truncated GLI1 (tGLI1) activation signatures are co-enriched in triple-negative subtypes and HER2-subtypes of breast cancers. High levels of STAT3 and GLI1/tGLI1 co-activation leads to worse prognosis. STAT3 [...] we revisited the question of the relationship between Cav1 and Stat3-ptyr705 in non-transformed mouse fibroblasts and in human lung carcinoma cells, by examining their effect at different cell densities.Our results demonstrate that Cav1 downregulates [...] our data demonstrate that hypoxia strongly potentiates the peroxide-mediated induction of hepcidin via STAT3 signaling pathway. Moreover, oxidases such as NOX4 or artificially overexpressed urate oxidase (UOX) can induce hepcidin G6PD contributes to HCC migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition through activation of signal transducer and activator of transcription 3 Systemic IFN activation is associated with higher activity only in the ESSDAI biological domain but not in other domains or the total score. Our data raise the possibility that the ESSDAI biological domain score may be a more sensitive endpoint for t [...] STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles. ERRalpha suppression inhibited signal transducer and activator of transcription (STAT3) protein expression. Data show that the secretion profile of PC3 prostate-cancer cells induces a change in macrophage phenotype from M1 into M2 is related to phosphorylation of transcription factor STAT3. STAT3 activation via Tyr705 phosphorylation plays role in he tumor-associated macrophage polarization. in oral tumor cells, overexpression of cyclin D1 occurs through the activation of STAT3 and the deregulation of degradation pathway of cyclin D1 which may favors maintaining its accumulated level in cells. It also demonstrated that cyclin D1 expressi [...] STAT3 regulates angiogenic and metabolic pathways before HIF1alpha, suggesting that HIF1alpha is not the initiating trans-acting factor in the response of pericytes to ischemia. Simultaneous inactivation of EAF2 and p53 can act to activate STAT3 and drive prostate tumorigenesis. High STAT3 expression is associated with cholangiocarcinoma. Acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation. The results indicated that when STAT3 signaling activity was attenuated by Stattic or enhanced with a STAT3 plasmid, the EZH2/miR-200 axis was markedly altered, thus resulting in modulation of the invasion and migration of OSCC cell lines. IL-33 may down-regulate CLDN1 expression through the ERK/STAT3 pathway in keratinocytes. Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating [...] HDAC3 is an important regulator of STAT3-dependent cell proliferation in liver regeneration and cancer. MerTK mediates STAT3-KRAS/SRC-signaling axis for glioma stem cell maintenance LncRNA PTCSC3 was low-expressed in anaplastic thyroid cancer (ATC) tissues and cells. Over-expressed PTCSC3 inhibited the drug resistance of ATC to doxorubicin. PTCSC3 negatively regulated STAT3, and STAT3 promoted expression of INO80. PTCSC3 regulat [...] the effect of the STAT3 inhibitor SH-4-54 on GBM migration and survival. SH-4-54 inhibited STAT3 activity and reduced 3D migration and survival of GBM43 but had no effect on GBM10. The suppression of STAT3 expression was associated with concomitant down regulation of IncRNA HOTAIR and had similar effects on the proliferation, migration and invasion of the cervical cancer cells that of HOTAIR. Study shows that high expression of IL22RA1 is associated with poor prognosis in pancreatic cancer. IL22 promotes pancreatic cancer stemness via IL22RA1/STAT3 signaling, identifying the mechanism of regulation of cancer stem cells by microenvironment [...] MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. IL-23 binding to its receptor promotes the migration and invasion of gastric cancer cells by inducing epithelial-to-mesenchymal transition through the STAT3 signaling pathway. we wanted to explore whether STAT3 can be related to lymph node micrometastasis of non-small cell lung cancer (NSCLC). To address this question, we evaluated the expression of MUC1 mRNA in the lymph node samples of NSCLC to determine micrometastasis. [...] Our results showed that IL-37 plays an inhibitory role in non-small cell lung cancer progression, possibly by suppressing STAT3 activation and decreasing epithelial-to-mesenchymal transition by inhibiting IL-6 expression. IL-37 could serve as a poten [...] Early hyperoxia exposure led to a significant increase in NOS3 and STAT3 mRNA levels in pulmonary endothelial cells with corresponding changes in histone modification patterns such as H2aZac and H3K9ac hyperacetylation at the respective gene loci. an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1 causing T cell exhaustion the transcription factor signal transducer and activator of transcription 3 was activated by TB-PE, and its chemical inhibition prevented the accumulation of lipid bodies and ACAT expression in macrophages. In terms of the host immune response, TB-PE [...] STAT3 rs1053004 and rs1053005 polymorphisms and haplotypes formed by rs1053004 and rs1053005 are associated with chronic HBV infection and the haplotypes appear to be also associated with the development of liver disease. Studied effect of carfilzomib and doxorubicin on IL-6, pSTAT-3 and NF-kB Activity in MDA-MB-231 Breast Cancer Cells. The upregulation of miR-21 may facilitate the odontoblast differentiation of dental pulp stem cells coordinating with STAT3. The inhibition of miR-21 (anti-miR-21) decreased the activation of STAT3 as well as suppressed the marker proteins of odontob [...] TNFRSF1A is a STAT3 target gene that regulates the NF-kappaB pathway. Increased STAT3 expression and phosphorylation is associated with HPV positive cervical disease. findings illustrate the significance of CREB-KDM4B-STAT3 signaling cascade in DNA damage response, and highlight that KDM4B may potentially be a novel oncotarget for colorectal cancer radiotherapy. Exosomes from patient-derived ascites ovarian cancer cell lines cultured under hypoxic conditions carried more potent oncogenic proteins-STAT3. Case Report: breast implant-associated anaplastic large cell lymphoma with dual JAK1/STAT3 mutations. In this context, we investigated in vivo study using the nitrosodiethyl amine (NDEA)-induced HCC model, which strengthened our previous findings by showing the blockade of the IL-6 mediated JAK2/STAT3 oncogenic signaling pathway. Our results from experiments suggest that the effects of IL-17 mediate activation of STAT3 signaling in breast cancer cells. Taken together, our study shows that myeloid-derived suppressor cells can be a new type of prognostic marker in breast cancer [...] These results suggested that stemness induction in SKOV3 cells by macrophages co-cultured with SKOV3-derived OCSLCs involved IL-8/STAT3 signaling. Downregulation of miR-340 inhibited GC cell proliferation, arrested cell cycle, and facilitated apoptosis through upregulating SOCS3 expression to suppress JAK-STAT3 signaling pathway. Study utilizing integrative analysis of transcriptomic, metabolomic, and clinical data propose a model of GOT2 transcriptional regulation, in which the cooperative phosphorylation of STAT3 and direct joint binding of STAT3 and p65/NF-kappaB to the pr [...] STAT3 inhibits cell migration and growth, and rescues IFN response through up-regulating STAT1 signal transduction in HepG2 hepatoma cells. PBX1 plays an oncogenic role in clear cell renal carcinoma via JAK2/STAT3 pathway STAT3 phosphorylation, while responsive to exogenous ligands on both soft and stiff matrices, is innately active on a stiff matrix in a ligand/receptor-independent, but ROCK- and JAK2-dependent fashion. Icaritin enhances MSC proliferation, chemotaxis to stromal cell-derived factor-1 and osteogenic differentiation through STAT-3 activation, with a consequential up-regulation in the expression and activity of CXCR4. Icaritin enhances STAT-3 phosphoryl [...] the activation of STAT3, a major tumourigenic IL-6 effector, was examined in adipose-derived stem cells conditioned medium treated endometrial cancer cells. overexpression of miR-498 suppresses Th17 cell differentiation by targeting STAT3 in rheumatoid arthritis patients H19 may serve as a competing endogenous RNA (ceRNA) to modulate STAT3 by attaching miR-17 in lung cancer The mechanism of PVT1-mediated angiogenesis via evoking the STAT3/VEGFA signalling axis. In summary, CAPE attenuates Nasopharyngeal carcinoma (NPC)cell proliferation and invasion by upregulating NDRG1 expression via MAPK pathway and by inhibiting phosphorylation of STAT3. Considering the poor prognosis of NPC patients with metastasis, CA [...] The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation. In this review, the roles of STAT3 in the pathogenesis, diagnosis, treatment and prognosis of leukemia are discussed in the aspects of cell proliferation, differentiation and apoptosis, with the aim to further clarify the roles of STAT3 in leukemia, [...] Secretome analysis revealed that Oct4 upregulated interleukin 24 (IL24) expression through STAT3 and NFkappaB signaling, and siRNA against IL24 increased IRinduced senescence, whereas recombinant human IL24 suppressed it. The results of the present s [...] a novel signal circuit of Stat3/Oct-4/c-Myc was identified for regulating stemness-mediated Doxorubicin resistance in triple-negative breast cancer LncRNA TUG1 interacting with miR-144 contributes to proliferation, migration and tumorigenesis through activating the JAK2/STAT3 pathway in hepatocellular carcinoma. Our data suggest that MKP1 expression can be differentially regulated by p38, JNK, and the TBK1-JAK2-STAT3 pathway after activation of toll-like receptor 4 (TLR4) Monocytes are activated by the vascular endothelium during hypertension, in part due to a loss of NO signalling and increased release of IL-6 and hydrogen peroxide by the dysfunctional endothelium and a parallel increase in STAT3 activation in adjace [...] PCNA functions as an oncogene in the progression of NSCLC through up-regulation of STAT3. In summary, we describe a patient with elevated IgE level, atopy, and fatal invasive aspergillosis associated with a de novo STAT3 splice-site mutation that results in nonsense mediated decay, STAT3 haploinsufficiency, and reduced STAT3 phosphorylation. STAT3 is not only a downstream effector of sorafenib, but also a key regulator of cellular sensitivity to sorafenib induced cell death Structural characterization of STAT3 for the purpose of development of anticancer therapies has been reported. (Review) High STAT3 Expression is associated with lung adenocarcinoma. The result of our study for the first time provides evidence that rs1053004 polymorphism is significantly associated with a decreased risk of Cardiopulmonary bypass-associated acute kidney injury in Iranian population, especially in older subjects. The role of mitochondrial Stat3 as regulator for lymphocyte function is reviewed. either oncogenic or a tumour suppressor [review] addition of colivelin, a STAT3 activator, instead of IL-6 and C2C12 conditioned medium, promoted the myogenic differentiation of adipose tissue-derived stem cells. Data suggest rac1 GTP-binding protein (RAC1-GTP) directly interacte with activators of transcription 3 (STAT3) to promote STAT3 phosphorylation, thus promoted epithelial-mesenchymal transition (EMT) of colorectal cancer (CRC) cells. The phosphor STAT3 expression was associated with adverse survival in squamous cell carcinoma, but not in the oesophageal adenocarcinoma patients. metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions MIS416-SS-siStat3 conjugates added to cell culture medium of monolayers of DCs in culture flasks successfully targeted Stat3 mRNA in DCs in vitro without transfection, downregulating Stat3 mRNA and protein levels. CXCR7 silencing inhibits the migration and invasion of human tumor endothelial cells derived from hepatocellular carcinoma by suppressing STAT3. Oct4 plays a vital role in the malignant progression of HCC cells through the survivin/STAT3 signaling pathway. Study reports two distinct homozygous nonsense mutations in exons 6 and 8 of ZNF341 in four consanguineous families with recurrent bacterial and fungal infections. ZNF341 mutations segregate with a phenotype resembling hyper-immunoglobulin E syndrome [...] Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3. PAG1 conferred inherent radioresistance by activating STAT3. MiR-29a down-regulation is correlated with drug resistance of nasopharyngeal carcinoma cell line CNE-1 and MiR-29a up-regulation decreases Taxol resistance of nasopharyngeal carcinoma CNE-1 cells possibly via inhibiting STAT3 and Bcl-2 expression. these data provide mechanistic insights into the regulation of FEZF1-AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its stability. Parthenolide also induced reactive oxygen species (ROS), but the increased ROS did not seem to contribute to the inhibition of JAK/STAT3 signaling. microRNA-30d mediated breast cancer invasion, migration, and epithelial-mesenchymal transition by targeting KLF11 and activating STAT3 pathway. gastric cancer cells may directly sustain and amplify the local pro-inflammatory response upon encountering activated macrophages and LPS via NF-kappaB and STAT3 signalling pathways, thereby promoting tumour progression. High STAT3 expression is associated with drug resistance in Chronic myeloid leukemia. There is a strong link between pri-miR-124-1 rs531564 and STAT3 rs1053023 and gastric cancer that may be pathogenic, and so worthy of further investigation. a significant role for PRMT1 in HCC progression and metastasis in vitro and in vivo via STAT3 signalling pathway activation. PRMT1 may be a potential novel prognostic biomarker and new therapeutic target for hepatocellular carcinoma. Human cytomegalovirus IE1 causes SOX2 downregulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Study reports that SMAD6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating PIAS3. Mechanically, SMAD6 interacts directly with PIAS3, and this interaction is [...] Melatonin reinforces the anticancer activity of sorafenib by downregulation of PDGFR-beta/STAT3 signaling pathway and melatonin receptor (MT)-mediated STAT3. FEZF1-AS1 acts as an oncogenic lncRNA in human hepatocellular carcinoma by promoting JAK2/STAT3 signaling-mediated epithelial mesenchymal transformation. FABP5 promotes tumor angiogenesis via activation of the IL6/STAT3/VEGFA signaling pathway in hepatocellular carcinoma. This study demonstrates that VB inhibits glioblastoma cell proliferation, migration, and invasion while promoting apoptosis via SHP-1 activation and inhibition of STAT3 phosphorylation. Downregulation of the lincRNA of the NED25 gene was associated with sepsis in patients by modulating the signaling pathways downstream of miR-125b/STAT3/PCT/NO signaling pathway. STAT3 protein expression is upregulated in human papillary thyroid cancers (PTC) and in thyroid carcinoma cell lines exposed to PLX4032, a BRAF inhibitor, inducing PTC resistance. High STAT3 expression is associated with invasion and lymph node metastasis in gastric cancer. decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 (STAT3) acetylation and phosphorylation, and STAT3 activation. CIRP mediates the activation of STAT3-Bag-1 signaling cascade via activating the Janus kinase family proteins and NF-kappaB signaling pathways upon UV irradiation. A critical role for APE1 induction in activating the EGFR-STAT3 signaling axis. these results indicated that STAT3-mediated downexpression of miR-579-3p caused resistance to vemurafenib. Our findings suggest novel approaches to overcome resistance to vemurafenib by combining vemurafenib with STAT3 sliencing or miR-579-3p overexpression. Study showed TESC as a novel regulator of c-Src/IGF1R-mediated STAT3 activation pathway, which enhances ALDH1 expression, consequently reinforces the cancer stem cell-like and radio-resistant properties. High STAT3 expression is associated with lung adenocarcinoma. High STAT3 expression is associated with cell growth, aggressiveness, metastasis in gastric cancer. High expression of iNOS and STAT3 in cells transfected with miR-34a mimic further validated it. STAT3 over-expression is associated with cisplatin resistance in cervical cancer; decreasing STAT3 can significantly promote the apoptosis of cervical cancer cells These results suggest that STAT3-mediated IP3R3 downregulation in the ER crucially contributes to its anti-apoptotic functions via modulation of Ca(2+) fluxes. The data point to a participation of Notch in stabilizing toll like receptor-mediated STAT3 activation and STAT3-mediated modulation of myeloid functional phenotype through induction of immune-suppressive PD-L1. We further demonstrate that RIP4-activated STAT3 binds CCL20 promoter region and regulates its expression. High phosphorylated STAT3 expression is associated with pancreatic ductal adenocarcinoma. Therefore, ANXA2 overexpression play a pivotal role in colorectal cancer invasiveness through Src/ANXA2/STAT3 pathway activation. In extranodal NK/T-cell lymphoma, STAT3 activation correlated significantly with PD-L1 expression. a positive feedback loop between miR-181b and STAT3 that regulated the Warburg effect in colon cancer was also demonstrated. This study suggested miR-181b/PIAS3/STAT3 axis as a novel target for colon cancer treatment. miR-216a up-regulation is associated with cisplatin resistance in ovarian cancer and this effect is mediated by PTEN. STAT3 is a regulator of miR-216a Strategies that inhibit miR-216a is a potential strategy for overcoming the cisplatin resistance in [...] The results reveal that the EGF-STAT3 signaling pathway promotes and maintains colorectal cancer (CRC)stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/beta-catenin signaling pathway, which is also responsible for cancer stem [...] This review discusses the upstream activators of STAT3 in skeletal muscles, with a focus on interleukin 6 (IL6) and transforming growth factor beta 1 (TGF-beta1). we validate that JAK2/STAT3 signaling is indeed activated in the human pancreatic cancer tissues and SZC015 also shows inhibitory effect on this signaling both in vitro and in vivo. These data suggest the potent effects of SZC015 on pancreatic cancer [...] Study findings indicated that STAT3 could be a cancer-promoting factor and potentially a significant prognostic factor in upper urinary tract urothelial carcinoma. lncRNA H19 is repressed during aging and controls endothelial cell senescence, proliferation, inflammatory activation and angiogenic sprouting by inhibiting STAT3 activation. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFbeta-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Data show that signal transducer and activator of transcription 3 (STAT3) governs head and neck squamous cell carcinoma (HNSCC) tumor cell motility through MALAT-1 long non-coding RNA (malat1)/miR-30a interaction. STAT3 enhances lysosomal acidification by stimulating the ATPase activity of the V1 domain in the assembled V-ATPase complex on the lysosomal membrane. The pY291-Fas is essential for the EGF-induced formation of the Fas-mediated nuclear EGFR/STAT3 signaling complex. Our study revealed that Licochalcone (LC)C directly interacts with JAK2 and its downstream signaling kinases, STAT3 to inhibit the catalytic activities of these kinases, thereby not only suppressing proliferation, but also inducing apoptosis in oral [...] These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade. In summary, STAT3 gene was a transcriptional regulator of FOXP1. Depleted STAT3 restrained cell proliferation and invasion, promoted cell apoptosis in glioma cells. This molecular mechanism between STAT3 and FOXP1 can serve as a therapeutic target fo [...] KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons resistance to MEKi is mediated through activation of STAT3, whereas TACE-AREG-EGFR-dependent activation of RAS pathway signaling confers resistance to STAT3 inhibition Results show that enhanced interleukin 6(IL-6)/phosphorylated STAT3 transcription factor (pSTAT3) signaling may contribute to promotion of follicular helper T (Tfh) cells Tfh cells, consequently skewing the ratio of Tfh to follicular regulatory T (Tf [...] MAZ is a potential therapeutic target to dampen STAT3 signaling in colon cancer. These results demonstrate that miR-125a could constrain cell migration, invasion, and regulate HAS1 expression in renal cell carcinoma cells by targeting STAT3. we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 [...] The miR-1181/STAT3 axis mediated PDGFBB-induced dysfunction in human PASMCs. In the presence of fusion protein-tyrosine kinases ITK-FER and ITK-SYK, signal transducer and activator of transcription 3 (STAT3) was highly phosphorylated and early activation antigen CD69 (CD69) was significantly elevated. Studied immunosuppressive effect of Rosemary extract by inhibiting STAT3 pathway in cultured lymphocytes. Results show that STAT3 modulates ABCC transporter levels and act synergistically with YB-1 to regulate chemoresistance and cell invasion of gastric cancer cells. Our study identified the STAT3 rs1053004 C/C as a high-risk genotype in MA (MISSED ABORTION) with lower survivin and VEGF transcription levels in the peripheral blood This article focus is on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. This review focus is on the distinct properties of the STAT3alpha and beta isoforms; the multiple post-translational modifications that can affect its activities downstream of multiple different signals; the non-canonical functions in the mitochondri [...] Macrophage-induced IL-6 promotes migration and invasion of colon cancer cell via Wnt/beta-catenin pathway in STAT3/ERK-dependent way. Suppressing IL-10 significantly reduced STAT3 activation in both MYD88 WT and MYD88 L265P mutant lymphomas. we confirmed that PCGEM1 could upregulate the expression of STAT3 by acting as a competing endogenous RNA for miR-129-5p, thereby affecting the occurrence and development of endometrial carcinoma PD-1(+)CD4(+) T cells with reduced proliferative capacity and increased transforming growth factor-beta (TGF-beta)/interleukin-17A (IL-17A) expression were detected in idiopathic pulmonary fibrosis. The cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expressing V561M demonstrate dramatic resistan [...] our results concluded that CASC9 promotes STAT3 expression via sponging miR-519d, in return, STAT3 activate CASC9 transcription, forming a positive feedback loop of CASC9/miR-519d/STAT3. The novel finding provides a potential therapeutic target for glioma. Description of the role of inherited STAT1 and STAT3 mutations in the setting of human disease with highly variable phenotypes that include immunodeficiency, malignancy, and autoimmunity (review). Through inhibition of the Stat3 signaling pathway. To achieve this, using semi-quantitative mass spectrometry, we found MUC1 to be significantly and durably upregulated in response to erlotinib, an EGFR-targeting treatment. MUC1 upregulation was regulated transcriptionally, involving PI3K-signaling and STAT3 Ruxolitinib-treated tumors in both the immunocompromised and immunocompetent animal models demonstrate decreased phospho-STAT3, indicating on-target activity. In conclusion, CA-MSC activate ovarian cancer cell STAT3 signaling via IL6 and LIF and incr [...] this study reports that eosinophilia and reduced STAT3 signaling affect neutrophil cell death in autosomal-dominant Hyper-IgE syndrome S1PR1-STAT3 signaling may participate drug resistance in gastric cancer (GC), thus could serve as a drug target to increase the efficacy of GC treatment. Interleukin-35 (IL-35)-mediated promotion of interleukin 10 (IL-10) required STAT3 transcription factor (STAT3) phosphorylation. LINC01433 participated in hepatocellular carcinoma progression through modulating the miR-1301/STAT3 axis data demonstrate that nicotine induced IL-6 expression, which, in turn, enhanced the invasiveness of endothelial EA.hy926 cells, via activation of the p38 MAPK/AP-1 and ROS/STAT-3 signaling pathways. these results suggest that STAT3 activation maybe related to vemurafenib sensitivity in colon cancer cells, and that combining STAT3 inhibitors with vemurafenib may be a promising treatment for BRAF(V600E) mutant colon cancers. IL-6, TNF-alpha production, SOCS3 mRNA expression were downregulated, while miR-196b-5p and STAT3 mRNA expression were upregulated in monocytes from long-term cigarette smoking-related pulmonary tuberculosis patients as compared to nonsmoking pulmona [...] Hepatitis C virus core protein maintains immunosuppression by promoting IL-10/STAT3-dependent differentiation of G-Myeloid-derived suppressor cells from PBMCs, resulting in the impaired functioning of T-cells. YAP interacts with STAT3 to promote the phosphorylation, nuclear translocation and VEGF transcription of STAT3, hence facilitates the proliferation, migration and tube formation of retinal microvascular endothelial cells. Authors proved that TAMs possess the ability to promote OS cell migration and invasion by upregulating COX-2, MMP9, and phosphorylated STAT3 and to induce the epithelial-mesenchymal transition (EMT). the decrease of miR-21 associated proteins phosphorylated STAT3 and E2F3 was seen in GAS5 overexpressed cells, both of which could be increased by sirna GAS5. I157172 induced upregulation of SIRT1, and downregulation of acetyl-STAT3. High STAT3 expression is associated with aerobic glycolysis and proliferation in breast cancer. SOCS3 overexpression rescued the IL-9-induced effects. Altogether, IL-9 participates in the pathogenesis of Ulcerative colitis (UC) through STAT3/SOCS3 signaling pathway and has the potential to serve as a possible therapeutic candidate in patients with UC The findings indicate miR-874 as a contributory role in cardiac ischemia-reperfusion injury...by targeting STAT3 through the JAK2/STAT3 signaling pathway. HMGB1 silencing promotes tumor cells viability and arrest of pro-apoptotic proteins via Stat3/NFkappaB signaling in HepG2 cells. Results suggest that IL-22 promotes OS cells proliferation and invasion and its effect is mediated by activation of the STAT3 pathway. These findings identify a role of STAT3/mTOR-regulated autophagy in angiotensin II - induced senescence of human glomerular mesangial cells. These data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant Lung adenocarcinomas. High STAT3 expression is associated with liver cancer. High STAT3 expression is associated with oral squamous cell carcinoma. A significant positive correlation was demonstrated between STAT1 and STAT2 and also between STAT1 and STAT3. These findings support the notion that control of pSTAT3 in TCL tumors is complex and involves epigenetic silencing of the tyrosine phosphatase PTPN6. The protective microRNA-199a-5p-mediated unfolded protein response in hypoxic cardiomyocytes is regulated by STAT3 pathway. TSLP might promote asthmatic airway remodeling via p38 MAPK-STAT3 axis activation and the crosstalk between airway epithelial cells and fibroblasts could aggravate remodeling. Promoter regions of ZO-1 and SOCS3 were directly regulated by transcriptional activation of STAT3. These findings suggest that regulation of the STAT3 pathway is essential for corneal endothelial homeostasis via barrier function and may protect from [...] PLOD3 and the STAT3 pathway were significantly correlated in the metastatic foci of lung cancer patients; PLOD3-STAT3 levels were highly correlated with a poor prognosis. These results indicate that PLOD3 promotes lung cancer metastasis in a RAS-MAP [...] STAT3 could bind directly to the region between -547 bp to -537 bp (ATGTTGGGAAA) of LINC00165 promoter and activate its transcription. our study also showed that SIRT1 is the novel direct target of miR-194-5p in colorectal cancer (CRC) cells. Taken together, our study suggests that H19 mediates 5-Fu resistance in CRC via SIRT1 mediated autophagy. Our finding provides a novel mechani [...] This work has elucidated a novel mechanism of TNK2-AS1-mediated angiogenesis by enforcing STAT3/VEGFA signaling. Gene alteration and protein expression of PD-L1 and phosphor STAT3 expression were closely related in diffuse large B cell lymphoma. STAT3 was a direct and functional target of miR-874-3p in esophageal squamous cell carcinoma cells, regulating cell proliferation and migration. LSINCT5 could bind to HMGA2 and decrease proteasome-mediated HMGA2 degradation leading to EMT activation. LSINCT5 also served as a competing endogenous RNA (ceRNA) for miR-4516, resulting in increased STAT3/BclxL expression and attenuated apoptosis. Proliferation of rheumatoid arthritis fibroblast-like synoviocytes is enhanced by IL-17-mediated autophagy through STAT3 activation. it was found that LUCAT1 was activated by STAT3 and promoted cell proliferation, migration, and invasion in HB through modulation of the miR-301b/STAT3 axis. ARHGAP24 can suppress the development of MDA-MB-231 cells via the STAT3 signaling pathway, and sorafenib inhibits cell viability, migration, invasion, and STAT3 activation in MDA-MB-231 cells through ARHGAP24. High levels of cytosolic short form of ALR reduced CYP7A1 mRNA expression and bile acids levels attributed to STAT3 activation. expression level of JAK2/STAT3 mRNA increases signficanlty in chronic idiopathic thrombocytopenic purpura patients CASC11 was found to be activated by the transcription factor STAT3 in hepatocellular carcinoma cells Casticin inhibits growth and enhances ionizing radiation-induced apoptosis through the suppression of STAT3 signaling cascade. The STAT3 pathway promotes hepatocellular carcinoma (HCC) progression from two important aspects, stimulating the proliferation of HCC cells via VEGF/VEGFR positive feedback loop and VEGF secreted by HCC in turn promoting the proliferation, migration [...] We also found that Hsp90 and HDAC inhibitors could substantially and simultaneously suppress the proliferation of resistant cells, the secretion of multiple cytokines, and the activation of STAT3. SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3), in mantle cell lymphoma is reported. the effects of combination treatment of phosphatase activation with TKIs on cell number and activation of the signal transducer and activator of transcription 3 (STAT3) resistance pathway were determined. The combination of Rb phosphatase activation [...] High STAT3 expression is associated with Obesity. STAT3 phosphorylation was also enhanced by NTP treatment in injured animal muscle. miR-506 enhanced natural killer cell cytotoxicity against hepatocellular carcinoma cells by targeting STAT3. our findings demonstrate that defective glycosylation in PGM3-deficient patients results in reduced expression of unglycosylated gp130 protein and consequently, impaired gp130-dependent STAT3 phosphorylation. findings provide insight into the important role of SIRT2 in colon tumour angiogenesis and suggest that SIRT2/STAT3/VEGFA might be a novel prognostic biomarker and a potential therapeutic target for patients with colorectal cancer. The results of the present study demonstrated that EPDMNQ and ENDMNQ induced apoptosis through ROSmodulated MAPK and STAT3 signaling pathways in Hep3B cells. Therefore, these novel 1,4naphthoquinone derivatives may be useful as anticancer agents for [...] pSTAT3 is associated with longer relapse-free and overall survival and can be used as a prognostic tool for determination of group of breast cancer patients with low-risk. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated. High STAT3 expression is associated with lymph node metastasis and intrahepatic metastasis in Gallbladder Cancer. The inhibition of Tyr705 STAT3 constitutive phosphorylation by AG490 leads to the activation of p53-p21 axis and KSHV lytic cycle in PEL cells during inflammation, IFN-gamma regulates IL-6/STAT3 signaling in intestinal epithelial cells in the colonic mucosa Blocking the interaction between IL-6 and GP130 may inhibit the IL-6/GP130/STAT3 signaling pathway. ABHD11-AS1 acted as a competitive endogenous (ce) RNA to upregulate STAT3 by sponging miR-1301-3p. STAT3-induced lncRNA ABHD11-AS1 promoted papillary thyroid carcinoma progression by regulating PI3K/AKT signalling pathway and miR-1301-3p/STAT3 axis. Results show that the level of STAT3 phosphorylation is significantly upregulated in diabetic cardiomyopathy. LncRNA BLACAT1 contributes to the proliferation and migration of osteosarcoma cells by regulating STAT3 Scutellarin (SCU) can suppress proliferation and promote apoptosis in A549 cells through AKT/mTOR/4EBP1 and STAT3 pathways. This suggests that SCU may be developed into a promising antitumor agent for treating non-small cell lung cancer (NSCLC) Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors HoxA10 interacts with p38 MAPK to repress the activation of p38 MAPK and STAT3 and recruits and facilitates SHP-1 to catalyze the dephosphorylation of p38 MAPK and STAT3. Transcription factor STAT3 is activated upstream of IRF9 and binds to the IRF9 promoter in multicellular spheroids (MCS) of HCT116 colorectal carcinoma cells. STAT3 mediates expression of IRF9 and interferon stimulated genes The association between STAT3 single nucleotide polymorphism rs4796793 and susceptibility to lung cancer in Chinese lung cancer patients. These phenomena were associated with the suppression of BCSC-like characteristics and STAT3 dysfunction. There is a strong correlation with STAT-3 and Ki-67 in grade I and grade II meningiomas The LINC00518 acts as an oncogene in cervical cancer (CC) via regulation of the JAK/STAT3 signaling pathway. STAT3 participates in modulating G2-M phase checkpoint by regulating gene expressions of cyclin B1 and Cdc2 via E2F. This work identifies a miR-122-RTKs/STAT3-IRF1-IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. STAT3 gene is highly expressed in acute myeloid leukemia(AML) patients, which may be used as a predictor for high-risk of AML the results of the present study indicated that lncRNA H19/miR29b3p/STAT3 signaling was involved in the development of lung adenocarcinoma The anticancer effects of cisplatin by modulating the JAK/STAT3 signaling pathway. HSD17B4 overexpression increased STAT3 activation. There were higher intensities of pSTAT3/beta-actin and STAT3/beta-actin in systemic lupus erythematosus (SLE), and a positive correlation between IL-17 expression and pSTAT3/beta-actin or STAT3/beta-actin intensity. low expression of miR-340-5p in osteosarcoma (OS) and U2OS cells could inhibit the course of OS by negatively regulating Wnt/beta-catenin signaling pathway through targeting STAT3 gene; therefore, miR-340-5p might be a potential biomarker and target [...] EGF regulated HIF-1alpha through the STAT3 phosphorylation pathway, eventually promoting the occurrence and metastasis of colorectal cancer in SW480 cells study demonstrates how IL-22-induced activation of STAT3 synergizes with NF-kappaB-activating cytokines to enhance LCN-2 expression in human IECs and elucidates how ILC3 are involved in LCN-2-mediated host defense against Enterobacteriaceae. JAK/STAT3 and NF-kappaB Signaling Pathways Regulate Cancer Stem-Cell Properties in Anaplastic Thyroid Cancer Cells. These results indicate that AR occurs through the Src/MEK/ERK/STAT-3 pathway, activating VEGF-C expression and contributing to lymphangiogenesis in human chondrosarcoma. Thus, AR could be a therapeutic target in metastasis and lymphangiogenesis of ch [...] RORC-mediated regulation of a PD-L1/ITGB6/FAK/STAT3 signaling axis in bladder cancer. In the hypopharyngeal squamous cell carcinoma (HSCC) samples, low AIM2 expression was closely related to lymph node metastasis and intravascular tumor thrombus and were strongly associated with poor survival. AIM2 expression was negatively correlated [...] Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review. These results suggest that heterogeneity of Chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) and STAT3-mutated NK cells may play a significant role in cytopenia in CLPD-NK patients. We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 antisense oligonucleotide in the standard of care for cancer patients receiving radiation a functional role of ASS1 in HCC. Overexpression of ASS1 inhibits HCC progression by inactivating the pSTAT3Ser727 pathway, which subsequently decreases the expression of ID1. this study shows that constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients these data indicate that miR-124 suppresses the growth and invasion of breast cancer cells via downregulation of STAT3 expression. Data show that phosphorylated STAT3 could bind to the miR155HG promoter region from - 1548 bp to - 1411 bp upstream of the transcription start site to stimulate miR155HG expression. This suggests that STAT3 phosphorylation is the critical role in dri [...] MEST induces Twist-1-mediated EMT through STAT3 activation in breast cancers. Low pSTAT3(727) and pSTAT3(705) expression in epithelial cells of cancerous prostatic glands in hormone-naive PCa was associated with faster disease progression. However, pSTAT3 and tSTAT3 expression did not improve the prognostic value of Gleason sc [...] Histone deacetylase inhibitor FK228 treatment significantly reduced pYSTAT3 in primary Sezary syndrome (SS) cells and was partially mediated by RAD23B. SS cells harboring the common STAT3 Y640F variant were less sensitive to FK228-induced apoptosis. [...] Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers. Antrodia cinnamomea induces anti-tumor activity by inhibiting the STAT3 signaling pathway in lung cancer cells. STAT3 signalling pathway is implicated in keloid pathogenesis by preliminary transcriptome and open chromatin analyses. we proved that IL-6 might promoted endometrial carcinoma invasion and migration through activating the Stat3 signaling pathway. The expression of Stat3, Anxa2, or co-high-expression of the two proteins was associated with hepatocellular carcinoma recurrence and survival we demonstrated that IL-6 released during MG-GBM crosstalk leads to barrier dysfunction through the activation of the JAK/STAT3 pathway in endothelial cells (ECs) and downregulation of intercellular junction proteins Papilledema can occur as a manifestation of STAT3 gain-of-function mutation, sometimes accompanied by prominent vascular sheathing and cystoid macular edema. a critical role for STAT3 signaling in high glucose-induced EMT in HMrSV5 cells phosphatase and tensin homolog (PTEN) was recognized as a target of miR-21, and STAT3 inhibition restored AngII-induced reduction in PTEN. Similarly, the STAT3/miR-21 axis was shown to mediate AngII-provoked angiogenesis in vivo, which was demonstrat [...] Based on these results, FGF23 induces atrial fibrosis in patients with atrial fibrillation (AF) by increasing reactive oxygen species production and subsequently activating STAT3 and SMAD3 signaling. Knockdown of STAT3 did not affect basal proliferation, but reduced sphere forming capacity of two human melanoma cell lines. Moreover, the level of active STAT3 was elevated in rhodamine 123 negative subpopulations of CSCs sorted from three melanoma [...] MiR-630 inhibits papillary thyroid carcinoma cell growth, metastasis, and epithelial-mesenchymal transition by suppressing JAK2/STAT3 signaling pathway. PD-L1 expression was positively correlated with FGFR2 expression incolorectal cancer (CRC). Tumor-derived-activated FGFR2 induced PD-L1 expression via the JAK/STAT3 signaling pathway in human CRC cells results reveal a further level of complexity in the relationship between Cav1 and Stat3-ptyr705 than previously thought; in addition, we demonstrate that in a feedback loop, Stat3 inhibition upregulates Cav1 in HeLa cells but not in other lines tested Jagged1 (JAG1) can crosstalk with the JAK/STAT3 pathway. Hsa_circ_0068871 regulates the miR-181a-5p/FGFR3 axis and activates STAT3 to promote bladder cancer (BCa) progression, and it may serve as a potential biomarker. The present results revealed that the JAK3/STAT3 oncogenic pathway and PRDM1 expression could stratify clinicopathologic features of extranodal NK/Tcell lymphoma, nasal type (ENNK/TNT). our studies revealed that protein phosphotase CSTP1 inhibited IL-6 expression through targeting Akt/FoxO3a signaling pathway and IL-6 inactivated Stat3 was necessary for CSTP1's tumor suppressive function. the intracellular interaction of IL-32theta;, PKCdelta, and STAT3 to regulate IL-13 and IL-13Ralpha2 synthesis, supporting the role of IL-32theta; as an inflammatory modulator. STAT3 alternative splicing switch drives anti-tumorigenic outcomes in MCF10 human breast cancer cells. The proximal BIRC5 promoter possesses specific binding sites for key transcription factors such as nuclear factor kappaB and signal transducer and activator of transcription 3. Upregulation of survivin exacerbates the autoimmune diseases (AIDs) inclu [...] Study that STAT3 expression is regulated in colorectal neoplasm by PTPN4 which directly dephosphorylates pSTAT3 at the Tyr705 residue and suppresses its transcriptional activity. Potential natural source of anti-gastric cancer drugs via epigenetic mechanism to inhibit LncRNA-PVT1-STAT3 axis. findings suggested that CypB silencing may suppress the proliferation, invasion, migration and angiogenesis of A549 cells via inhibiting STAT3 pathway. NQO1-expressing, napabucasin-sensitive tumor cells can modify tumor cells and the TME to promote STAT3 phosphorylation, suggesting that pSTAT3 may be used to identify a subpopulation of patients who would likely respond to napabucasin. This study shows that cancer-bone microenvironment interactions lead to calcium-STAT3 signaling, which may present an area for therapeutic targeting of metastatic Prostate cancer. Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-kappaB and nuclear factor of activated T cells pathways. the findings of the present study suggested that MSI1 silencing can suppress oral squamous cell carcinoma cell proliferation and progression, in part by inhibiting the activation of the cMyc/STAT3 pathway. MAPK, Akt, and STAT3 pathways might play diverse roles in oral carcinogenesis reactive oxygen species could induce CD80 expression via the JNK and p38 MAPK pathways, that activated STAT3 transcription factor in colon cancer epithelial cells MPTDMNQ induced AGS cell apoptosis via ROS-mediated MAPK and STAT3 signaling pathways. Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer. Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8(+) T cells activation via JAK-STAT pathway in vitiligo. Prognostic values of STAT3 and HIF-1alpha in esophageal squamous cell carcinoma. Results suggested that STAT3 activity be requisite for the lung tumorigenesis caused by MVP knockdown. High STAT3 expression is associated with ovarian Cancer. HOXA11-AS regulates JAK-STAT pathway by miR-15a-3p/STAT3 axis to promote the growth and metastasis in liver cancer. Measurements of STAT1 and STAT3 phosphorylation on MSCs as responder cells correlate and predict allogeneic T-cell suppression. IL6induced activation of STAT3 target genes (e.g. MCL1 and BCL2) was attenuated by triptolide and homoharringtonine. Results suggested that ANXA2 may regulate the phosphorylation of STAT3 (Y705) levels through direct binding with STAT3, thereby affecting STAT3cyclin D1 pathwaymediated cell proliferation. STAT3 knockdown inhibits proliferation by downregulating cyclin D1. EMT/ZEB1 and IL-6/11-STAT3 signalling act independently and congregate to establish the expression pattern of S100 proteins, which drives invasion. SAA1 and cortisol can reinforce each other in the induction of 11beta-HSD1 expression through sequential phosphorylation of STAT3. STAT3 directly bound to the promoter of NKp46, an important activating receptor of NK cells, to regulate its transcription and expression. STAT3-induced LINC00668 contributed to non-small cell lung cancer progression through upregulating KLF7 expression by sponging miR-193a. The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with hepatocellular carcinoma (HCC). The present study also indicates that STAT4 rs7574865 polymorphism increased the r [...] By genetically encoding the co-translational incorporation of acetyl-lysine into position Lys685 and co-expression of STAT3 with the Elk receptor tyrosine kinase, we were able to characterize site-specifically acetylated, and simultaneously acetylate [...] Here, the authors report that Mycobacterium bovis BCG promotes IL-10 expression and cytokine production by establishing a SYK/PKCalpha/beta positive feedback loop that leads to STAT3 activation. Down-regulation of SOX18 inhibits laryngeal carcinoma cell proliferation, migration, and invasion through JAK2/STAT3 signaling. we found that lung cancer cells induced Adipose-derived mesenchymal stem cells (ADSCs) to secrete high levels of IL-6 family cytokines and activate the STAT3 signalling pathway FGB was the target gene of STAT3, and SIRT1 repressed the expression of FGB by deacetylation of STAT3. STAT3-mediated transcription of SMYD3 plays a role in promoting the progression of chronic lymphocytic leukemia This study presents a new upstream regulator of FOXL2 and demonstrats that this new STAT3-FOXL2 pathway has an important function in HeLaHeLa cell apoptosis, providing new insights regarding the targeting of FOXL2 for cancer prevention and treatment activation of the transcription factor NFkappaB, involving the small GTPase Rac1, is required for IL-6 production and subsequent STAT3 activation. the immunosuppressive effect of IL-10 on human macrophages is abrogated by endoplasmic reticulum stress through inhibition of STAT3 activation MicroRNA-301a promotes pancreatic cancer invasion and metastasis through the JAK/STAT3 signaling pathway by targeting SOCS5. High STAT3 expression is associated with proliferation and invasion in gastric cancer. the DARPP-32-IGF1R signaling axis plays a key role in regulating the STAT3 signaling, a critical step in gastric tumorigenesis STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of adult T-cell leukemia/lymphoma (ATLL), respectively. Phosphorylated STAT3 expression was significantly associated with better overall su [...] these results indicated that SSb2 may be a potential antitumor drug for the treatment of breast cancer, which acts by suppressing proliferation and migration by downregulating the STAT3 signalling pathway and inhibiting the expression of VASP, MMP2 a [...] Our findings further suggest that the antitumorigenic function of STAT3beta depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3 [...] Association of SP1 rs1353058818 and STAT3 rs1053004 gene polymorphisms with human tongue squamous cell carcinoma. STAT3 regulates a discrete set of genes in melanoma cells, including SERPINA3, a novel STAT3 target gene, which is functionally involved in regulation of melanoma migration and invasion. Knockdown of STAT3 impaired cell migration and invasion, in par [...] Knocking down eEF2K also led to a striking decrease in the phosphorylation of PI3K/Akt and STAT3, indicating inactivation of these tumorigenic pathways. Data suggest that eEF2K contributes to angiogenesis and tumor progression in HCC via SP1/KLF5-me [...] STAT3 activation in circulating immune cells contributes to retinal microvascular degeneration in diabetes mellitus. Authors showed that NEAT1 functions as an oncogenic sponge for the tumor suppressor microRNA-361 (miR-361), which suppresses proliferation, invasion, sphere formation and TX resistance by directly targeting the oncogene STAT3. Tanshinone I inhibits the growth and metastasis of osteosarcoma via suppressing JAK/STAT3 signalling pathway. results provide evidence that low vitamin D status is correlated with hyper-activation of cancerous IL-6/STAT3 and proliferation in clear cell renal cell carcinoma patients Functional annotation of noncoding causal variants in autoimmune diseases. ARHGAP15 regulates lung cancer cell proliferation and metastasis via the STAT3 pathway. MiR-124 changes the sensitivity of lung cancer cells to cisplatin through targeting STAT3. MiR-296-5p inhibits cell invasion and migration of esophageal squamous cell carcinoma by downregulating STAT3 signaling. Role of STAT3 in Resistance of Non-small Cell Lung Cancer IL-23-induced activation of STAT3 in the CD117(-)NKp44(-) ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher [...] Results demonstrated that NEAT1 and STAT3 expression levels were elevated in breast cancer, whereas miR124 was significantly reduced. NEAT1 overexpression markedly increased STAT3 protein expression levels, and this effect was reversed by miR124 over [...] Tumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy. Our results reveal a novel mechanism by which p-STAT3-containing exosomes contribute to acquired 5-FU resistance in colorectal cancer. This study suggests a new option for potentiating the 5-FU response and finding biomarkers for chemotherapy resistance. High STAT3 expression is associated with Multiple Myeloma. CC genotype in STAT3 rs2293152 polymorphism was associated with increased risk and GC genotype with decreased risk of basal cell carcinoma (BCC) in patients from northern Poland. C allele in STAT3 rs2293152 and G allele in STAT3 rs4796793 polymorphis [...] They also show that autosomal dominant form of hyper IgE syndrome-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3. the gene silencing efficacy showed a synergistic effect when combining STAT3/Notch-1 and STAT3/Notch-1/beta-catenin siRNA. Interestingly, the chemosensitivity of MCF7_DoxS and MCF7_DoxR cells to doxorubicin was increased when combined with siRNA trea [...] Progranulin, a STAT3 cofactor, is upregulated in colorectal canc as compared to nontumor tissue/cells and its expression correlates with STAT3 activation. Progranulin physically interacts with STAT3 in colorectal cancer, and its knockdown with a spec [...] EZH2 promotes invasion and tumour glycolysis by regulating STAT3 and FoxO1 signalling in human OSCC cells. These data demonstrate that IL-11 has a central role in postsurgical HCC recurrence, and that inhibition of IL-11-STAT3 signaling is a potential therapeutic strategy to prevent recurrence. Clinicopathological and Prognostic Role of STAT3/p-STAT3 in Breast Cancer Patients in China: A Meta-Analysis. High expression of STAT3 is associated with growth and invasion of ovarian cancer. IL-19 Up-Regulates Mucin 5AC Production in Patients With Chronic Rhinosinusitis via STAT3 Pathway. PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma. Inhibition of IGF-1R and STAT3 sensitizes STAT3-low cells and improves survival in mice. Myeloid maturation potentiates STAT3-mediated atypical IFN-gamma signaling and upregulation of PD-1 ligands in AML and MDS. The studies demonstrate for the first time that the function of MMP2 and MMP9 in breast cancer cell migration, which is mediated by interactions between ERalpha-36 and STAT3. IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in multiple myeloma with 1q21 amplification. High STAT3 expression is associated with hepatocellular carcinoma progression. The research first showed that p-STAT3 (Tyr 705) could bind to the promotor region of ERR-alpha and promote epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) by ZEB1 pathways, thus providing a potential clinical target for TNBC. Down-regulated circPAPPA suppresses the proliferation and invasion of trophoblast cells via the miR-384/STAT3 pathway. High STAT3 expression is associated with esophageal squamous cell carcinoma. The LINC00997-STAT3-S100A11 axis may promote the development of kidney renal clear cell carcinoma. Signal transducer and activator of transcription 3 (STAT3) was identified as a novel transcription factor that can directly and positively regulate both the transcription of E3 ubiquitin-protein ligase NEDD4 (NEDD4) and translation that follows. DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild-type NSCLC cells to AZD9291. Signal transducer and activator of transcription-3 drives the high-fat diet-associated prostate cancer growth. Genetic ablation of pS-STAT3 in the gp130 (F/F) human gastric cancer cell line xenografts abrogated tumor growth that coincided with reduced proliferative potential of the tumor epithelium. There is a hitherto unknown transcriptional role and obligat [...] Hypoxia induces rapid, STAT3 and ROS dependent, mitochondrial translocation of RelA(p65) and IkappaBalpha. bioinformatics analysis and in vitro experiments indicated that the role of KLF3 in lung cancer metastasis is dependent on the STAT3 signaling pathway. Overall, our data indicated the crucial function of KLF3 in lung cancer metastasis and suggested o [...] High level of active STAT3 expression and HPV genome copy number, and integrated state of the virus is associated with promotion/maintanence of cervical tumorigenic phenotype. STAT3-CyPA signaling pathway in endothelial cell apoptosis. ANGPTL4 partially modulates STAT3 and could serve as an effective diabetic retinopathy treatment strategy. STAT3/SHMT2/PKM2 loop in LNCaP cells can modulate a metabolic shift in response to inflammation at early stages of cancer progression, whereas a non-canonical STAT3 activation involving the STAT3/HIF-1alpha/PKM2 loop is responsible for the maintenanc [...] Reciprocal regulation of miR-206 and IL-6/STAT3 pathway mediates IL6-induced gefitinib resistance in EGFR-mutant lung cancer cells. we first identified JAK2/STAT3/CCND2 signaling as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients. CPAP promotes angiogenesis and metastasis by enhancing STAT3 activity. Study discovered a role of EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma. EIF3F promotes lung cancer cell metastasis in vivo by regulating a cluster of 34 metastasis-promoting genes inclu [...] A transcriptome analysis of the immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSCs) from pancreatic ductal adenocarcinoma cohort highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppress [...] Expression of miR-29 and STAT3 in osteosarcoma and its effect on proliferation regulation of osteosarcoma cells. High STAT3 expression is associated with metastasis of colorectal cancer. High STAT3 expression is associated with epithelialmesenchymal transition in head and neck squamous cell carcinoma. revealed that the SHP-1 methylation rate was positively correlated with the positive rate of STAT3 phosphorylation ELTD1 facilitates glioma proliferation, migration and invasion by activating JAK/STAT3/HIF-1alpha signaling axis. Phospho-Ser727 triggers a multistep inactivation of STAT3 by rapid dissociation of pY705-SH2 through C-terminal tail modulation. MYC and STAT3 may be the key regulatory genes in the underlying dysfunction of sepsis-induced acute respiratory distress syndrome. FASN may promote the metastasis of liver cancer by interacting with STAT3 and affecting the expression of MMP-2/MMP-9. PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies. STAT3-induced upregulation of lncRNA SNHG17 predicts a poor prognosis of melanoma and promotes cell proliferation and metastasis through regulating PI3K-AKT pathway. STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against epidermal growth factor receptor-tyrosine kinase inhibitors-resistant lung cancers. STAT3, tumor microenvironment, and microvessel density in diffuse large B cell lymphomas. miR4500 suppressed the cell proliferation, migration, invasion and promoted apoptosis of the human nonsmall cell lung cancer cell lines A549 and H1975. Expression of STAT3 was negatively correlated with miR4500 expression in vivo. miR4500 directly ta [...] Regulation of JAK/STAT signal pathway by miR-21 in the pathogenesis of juvenile idiopathic arthritis. The STAT3 is constitutively activated in CLL, induces Wnt5a signaling, we wondered whether STAT3 induces the expression of Wnt5a in CLL cells. The expression of circ_0076305 was found to have positive correlation with STAT3, and circ_0076305 was validated to regulate STAT3 via targeting miR-296-5p. The present study illustrated that circ_0076305 regulated STAT3 expression and DDP resistance [...] miR-383 may play a anti-tumor role in the pathogenesis of hepatocellular carcinoma by targeting IL-17 through STAT3 signaling pathway. on the whole, the findings of this study demonstrate that Gln promotes the proliferation of the Glndependent bladder cancer cell line, T24, by supplementing adenosine triphosphate (ATP) production and neutralizing ROS to activate the STAT3 pathway. The transcriptional response of GPR81 to lactate is mediated by Signal transducer and activator of transcription 3 (STAT3). TRIM14 exerted its oncogenic activities in papillary thyroid carcinoma via promoting the activation of STAT3 ANRIL is involved in hepatocellular carcinoma progression by direct targeting of miR-384 and STAT3. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. A self-enforcing HOXA11/Stat3 feedback loop promotes stemness properties and peritoneal metastasis in gastric cancer cells. The results from the present study suggested that quinalizarin induced G2/M phase cell cycle arrest and apoptosis in MCF7 cells through ROSmediated MAPK, STAT3 and NFkappaB signaling pathways. Via blocking the activation of STAT3. Differential expression of STAT3 gene and its regulatory long non-coding RNAs, namely lnc-DC and THRIL, in two eastern Iranian ethnicities with multiple sclerosis. C-X-C chemokine receptor 2 correlates with unfavorable prognosis and facilitates malignant cell activities via activating JAK2/STAT3 pathway in non-small cell lung cancer. Viral IL-10 promotes cell proliferation and cell cycle progression via JAK2/STAT3 signaling pathway in nasopharyngeal carcinoma cells. Costunolide suppresses STAT3 downstream target genes expression. Stat3 mutations impact on overall survival in large granular lymphocyte leukemia: a single-center experience of 205 patients. Overexpression of RPN2 promotes osteogenic differentiation of hBMSCs through the JAK/STAT3 pathway. TRIM27 expression is significantly increased by IL-6 and suggest a TRIM27/STAT3-dependent mechanism. VGLL4 interacts with STAT3 to function as a tumor suppressor in triple-negative breast cancer miR-29a-5p/STAT3 Positive Feedback Loop Regulates TETs in Colitis-Associated Colorectal Cancer. knockdown enhanced DC-SIGN expression in GC cells, further activating the JAK2/STAT3 signaling pathway. DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. MicroRNA-15a inhibits inflammatory response and apoptosis after spinal cord injury via targeting STAT3. Study highlights that exosomal ZFAS1 promotes the proliferation, migration and invasion of ESCC cells and inhibits their apoptosis by upregulating STAT3 and downregulating miR-124, thereby resulting in the development of tumorigenesis of ESCC. Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation. Targeting the activation of Stat3 may be a potential therapeutic approach for epithelial ovarian cancer by acting synergistically with paclitaxel. Respiratory syncytial virus reduces STAT3 phosphorylation in human memory CD8 T cells stimulated with IL-21. This review focuses on sesquiterpene lactones able to downmodulate STAT3 signaling leading to an antitumor effect and correlates the anti-STAT3 activity with their ability to decrease GSH levels in cancer cells. These properties make them lead compou [...] Nucleostemin promotes hepatocellular carcinoma by regulating the function of STAT3. Tannic acid and vitamin E loaded PLGA nanoparticles ameliorate hepatic injury in a chronic alcoholic liver damage model via EGFR-AKT-STAT3 pathway. Computational STAT3 activity inference reveals its roles in the pancreatic tumor microenvironment. IL-17 Induced Stromal Cell-Derived Factor-1 and Profibrotic Factor in Keloid-Derived Skin Fibroblasts via the STAT3 Pathway. Data demonstrated that ITGA2 interacted with STAT3 and up-regulated the phosphorylation of STAT3; this interaction might involve the mechanism of ITGA2 inducing PD-L1 expression in cancer cells. Integrin alpha6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells. We showed that serotonin, through 5-HTR2A/C, interferes with breast cancer cells proliferation and metabolism by triggering two distinct signalling pathways: Jak1/STAT3 that boosts glycolysis through upregulation of PKM2, and adenylyl cyclase/PKA tha [...] Functional Genomics Identifies Hepatitis-Induced STAT3-TYRO3-STAT3 Signaling as a Potential Therapeutic Target of Hepatoma. KIF20A promotes cellular malignant behavior and enhances resistance to chemotherapy in colorectal cancer through regulation of the JAK/STAT3 signaling pathway. IL-6 trans-signaling drives a STAT3-dependent pathway which stimulates a profibrotic signaling pathway, inflammatory response, and angiogenesis resulting in peritoneal fibrosis. Signal transducer and activator of transcription 3 (STAT3) phosphorylation regulates thromboxane A2 receptor activity in human platelets. Stat-3 signaling promotes cell proliferation and metastasis of gastric cancer through PDCD4 downregulation. Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression. STAT3-induced up-regulation of lncRNA NEAT1 as a ceRNA facilitates abdominal aortic aneurysm formation by elevating TULP3. microRNA cluster MC-let-7a-1~let-7d promotes autophagy and apoptosis of glioma cells by down-regulating STAT3. MiR-20a-5p suppressed TGF-beta1-triggered apoptosis of human bronchial epithelial BEAS-2B cells by targeting STAT3. MicroRNA-130a enhances the killing ability of natural killer cells against non-small cell lung cancer cells by targeting signal transducers and activators of transcription 3. Natural killer T cell cytotoxic activity in cervical cancer is facilitated by the LINC00240/microRNA-124-3p/STAT3/MICA axis. Long noncoding RNA BHLHE40-AS1 promotes early breast cancer progression through modulating IL-6/STAT3 signaling. Suppressing the metastatic properties of the breast cancer cells using STAT3 decoy oligodeoxynucleotides: A promising approach for eradication of cancer cells by differentiation therapy. BHLHE40 upregulation in gastric epithelial cells increases CXCL12 production through interaction with p-STAT3 in Helicobacter pylori-associated gastritis Alpha-lipoic acid inhibits both proliferation and invasion of gastric cancer cells by suppression of STAT3-mediated MUC4 gene expression Devastating Gynecological Infections in Women with STAT3 Deficiency. miR-125a regulates HAS1 and inhibits the proliferation, invasion and metastasis by targeting STAT3 in non-small cell lung cancer cells. Activation of STAT-3 signalling by RECK downregulation via ROS is involved in the 27-hydroxycholesterol-induced invasion in breast cancer cells. Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis. Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes. STAT3 expression was found to have significantly higher correlation with luminal breast cancer Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial-Mesenchymal Transition. STAT3 signaling statuses determine the fate of resveratrol-treated anaplastic thyroid cancer cells. Long noncoding RNA FOXD2-AS1 enhances chemotherapeutic resistance of laryngeal squamous cell carcinoma via STAT3 activation. LncRNA GAS5 inhibits Th17 differentiation and alleviates immune thrombocytopenia via promoting the ubiquitination of STAT3. Human omental adipose-derived mesenchymal stem cells enhance autophagy in ovarian carcinoma cells through the STAT3 signalling pathway. TGF-beta-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission. Silencing of IL-6 and STAT3 by siRNA loaded hyaluronate-N,N,N-trimethyl chitosan nanoparticles potently reduces cancer cell progression. These results suggest that CXCL16 produced through Ror2-mediated signaling in mesenchymal stem or stromal cells (MSC) within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate the CXCR6-STAT3 pathway, which, in turn, ind [...] The effect of single nucleotide polymorphisms of STAT3 on epilepsy in children. CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway. By modulation of STAT3 and NF-varkappaB. Downregulation of BIS sensitizes A549 cells for digoxin-mediated inhibition of invasion and migration by the STAT3-dependent pathway. ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis. Master and servant: LINC00152 - a STAT3-induced long noncoding RNA regulates STAT3 in a positive feedback in human multiple myeloma. The eEF2 kinase-induced STAT3 inactivation inhibits lung cancer cell proliferation by phosphorylation of PKM2. ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer. MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness. Folate receptor-targeted RNAi nanoparticles for silencing STAT3 in tumor-associated macrophages and tumor cells. Unphosphorylated STAT3 in heterochromatin formation and tumor suppression in lung cancer. Targeting STAT3 enhances NDV-induced immunogenic cell death in prostate cancer cells. Tissue Profile of CDK4 and STAT3 as Possible Innovative Therapeutic Targets in Urinary Bladder Cancer. Laminin 521 enhances self-renewal via STAT3 activation and promotes tumor progression in colorectal cancer. Role of STAT3 signaling pathway in breast cancer. Low phosphorylation level of STAT3 is associated with lung adenocarcinoma. STAT3-induced upregulation of circCCDC66 facilitates the progression of non-small cell lung cancer by targeting miR-33a-5p/KPNA4 axis. Thymoquinone induces apoptosis of human renal carcinoma Caki-1 cells by inhibiting JAK2/STAT3 through pro-oxidant effect. A Model of Differential Mammary Growth Initiation by Stat3 and Asymmetric Integrin-alpha6 Inheritance. Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth. Study found that loss of hsa_circ_0061140 significantly restrained endometrial carcinoma (EC) cells progression. hsa_circ_0061140 could act as a molecular sponge for miR-149-5p. STAT3 was predicted as a downstream target gene of miR-149-5p and miR-14 [...] TAB3 upregulates PIM1 expression by directly activating the TAK1-STAT3 complex to promote colorectal cancer growth. Feedback activation of EGFR is the main cause for STAT3 inhibition-irresponsiveness in pancreatic cancer cells. Cancer-associated adipocyte-derived G-CSF promotes breast cancer malignancy via Stat3 signaling. MiR-599 regulates LPS-mediated apoptosis and inflammatory responses through the JAK2/STAT3 signalling pathway via targeting ROCK1 in human umbilical vein endothelial cells. Long noncoding RNA HOST2, working as a competitive endogenous RNA, promotes STAT3-mediated cell proliferation and migration via decoying of let-7b in triple-negative breast cancer. Annexin A2-STAT3-Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma. The polymorphisms of IL-6/STAT3 signaling pathway may contribute to cutaneous T-cell lymphomas susceptibility. Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma. A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway. TIRC7 inhibits Th1 cells by upregulating the expression of CTLA4 and STAT3 in mice with acute graftversushost disease. Association of IL27 and STAT3 genetic polymorphism on the susceptibility of tuberculosis in Western Chinese Han population. Downregulation of SETD7 promotes migration and invasion of lung cancer cells via JAK2/STAT3 pathway. STAT3-dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer. Long non-coding RNA MALAT1 aggravates human retinoblastoma by sponging miR-20b-5p to upregulate STAT3. Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility. JAK1/STAT3 regulatory effect of beta-caryophyllene on MG-63 osteosarcoma cells via ROS-induced apoptotic mitochondrial pathway by DNA fragmentation. Long noncoding RNA LINC00324 promotes retinoblastoma progression by acting as a competing endogenous RNA for microRNA-769-5p, thereby increasing STAT3 expression. Calcitonin gene-related peptide inhibits angiotensin II-induced NADPH oxidase-dependent ROS via the Src/STAT3 signalling pathway. Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastasis and metabolic switch via PDK4-mediated STAT3/AKT/NF-kappaB/IL-8 signalling in ovarian cancer. Effects of STAT3 polymorphisms and pharmacokinetics on the clinical outcomes of gefitinib treatment in patients with EGFR-mutation positive non-small cell lung cancer. Overexpression of RPN2 suppresses radiosensitivity of glioma cells by activating STAT3 signal transduction. Ectopic PD-L1 expression in JAK2 (V617F) myeloproliferative neoplasm patients is mediated via increased activation of STAT3 and STAT5. The long non-coding RNA LINC00473 contributes to cell proliferation via JAK-STAT3 signaling pathway by regulating miR-195-5p/SEPT2 axis in prostate cancer. The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes. Vitexin abrogates invasion and survival of hepatocellular carcinoma cells through targeting STAT3 signaling pathway. IRF4 and STAT3 activities are associated with the imbalanced differentiation of T-cells in responses to inhalable particulate matters. The emergence of azole-resistant A. fumigatus infections in STAT3-deficiency dramatically impacts both curative and prophylactic antifungal strategies. Arginase-II promotes melanoma migration and adhesion through enhancing hydrogen peroxide production and STAT3 signaling. The interaction of interleukin-8 and PTEN inactivation promotes the malignant progression of head and neck squamous cell carcinoma via the STAT3 pathway. Brn3a/Pou4f1 Functions as a Tumor Suppressor by Targeting c-MET/STAT3 Signaling in Thyroid Cancer. Regulation of signal transducer and activator of transcription 3 activation by dual-specificity phosphatase 3. High frequency of STAT3 gene mutations in T-cell receptor (TCR)gammadelta-type T-cell large granular lymphocytic leukaemia: implications for molecular diagnostics. ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma. Computational and in vitro characterization of ICY-5: A potential candidate promoting mitochondrial apoptosis via the c-MET and STAT3 pathways. Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition. Transcription activation of circ-STAT3 induced by Gli2 promotes the progression of hepatoblastoma via acting as a sponge for miR-29a/b/c-3p to upregulate STAT3/Gli2. STAT3-mediated MLST8 gene expression regulates cap-dependent translation in cancer cells. Piperine inhibits colorectal cancer migration and invasion by regulating STAT3/Snail-mediated epithelial-mesenchymal transition. Pentadecanoic Acid, an Odd-Chain Fatty Acid, Suppresses the Stemness of MCF-7/SC Human Breast Cancer Stem-Like Cells through JAK2/STAT3 Signaling. Th17 cells inhibit CD8(+) T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients. CD109 mediates tumorigenicity and cancer aggressiveness via regulation of EGFR and STAT3 signalling in cervical squamous cell carcinoma. Low shear stress regulates vascular endothelial cell pyroptosis through miR-181b-5p/STAT-3 axis. ACYP2 contributes to malignant progression of glioma through promoting Ca(2+) efflux and subsequently activating c-Myc and STAT3 signals. IL-23R in laryngeal cancer: a cancer immunoediting process that facilitates tumor cell proliferation and results in cisplatin resistance. Loss of ZIP facilitates JAK2-STAT3 activation in tamoxifen-resistant breast cancer. MiR-126 promotes esophageal squamous cell carcinoma via inhibition of apoptosis and autophagy. In normal high-density neutrophils, the formation of acidic vesicular organelles, a morphological characteristic of autophagy, could be induced after exposure for three hours with myeloma conditioned media or MM sera, an effect associated with increa [...] Effect of STAT3 mediated epigenetic regulation in pre-eclampsia: an analysis of trial data. STAT3 modulates reprogramming efficiency of human somatic cells; insights from autosomal dominant Hyper IgE syndrome caused by STAT3 mutations. CXCR4-STAT3 Axis Plays a Role in Tumor Cell Infiltration in an Orthotopic Mouse Glioblastoma Model. Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels. Long Noncoding RNA SNHG16 Facilitates Abdominal Aortic Aneurysm Progression through the miR-106b-5p/STAT3 Feedback Loop. Silencing Stat3 inhibits viability and induces apoptosis in BGC-823 human gastric cancer cell line. DTNA promotes HBV-induced hepatocellular carcinoma progression by activating STAT3 and regulating TGFbeta1 and P53 signaling. Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation. Columbamine suppresses proliferation and invasion of melanoma cell A375 via HSP90-mediated STAT3 activation. IL6/STAT3 Signaling Hijacks Estrogen Receptor alpha Enhancers to Drive Breast Cancer Metastasis. Osteal Tissue Macrophages Are Involved in Endplate Osteosclerosis through the OSM-STAT3/YAP1 Signaling Axis in Modic Changes. A frequent somatic mutation in the 3'UTR of GAPDH facilitates the development of ovarian cancer by creating a miR125b binding site. Effect of malignant-associated pleural effusion on endothelial viability, motility and angiogenesis in lung cancer. MicroRNA-340-5p suppressed rheumatoid arthritis synovial fibroblast proliferation and induces apoptotic cell number by targeting signal transducers and activators of transcription 3. Large granular lymphocyte leukemia serum and corresponding hematological parameters reveal unique cytokine and sphingolipid biomarkers and associations with STAT3 mutations. Mechanical pain of the lower extremity after compression of the upper spinal cord involves signal transducer and activator of transcription 3-dependent reactive astrocytes and interleukin-6. Trophoblast-derived IL-6 serves as an important factor for normal pregnancy by activating Stat3-mediated M2 macrophages polarization. RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC. LncRNA PVT1 induces aggressive vasculogenic mimicry formation through activating the STAT3/Slug axis and epithelial-to-mesenchymal transition in gastric cancer. Differentially localized survivin and STAT3 as markers of gastric cancer progression: Association with Helicobacter pylori. Identification of putative phenotype-modifying genetic factors associated with phenotypic diversity in Brooke-Spiegler syndrome. (Immunohistochemical study of STAT3, HIF-1alpha and VEGF in pterygium and normal conjunctiva: Experimental research and literature review). Cell migration inducing hyaluronidase 1 (CEMIP) activates STAT3 pathway to facilitate cell proliferation and migration in breast cancer. Lupus-like autoimmunity and increased interferon response in patients with STAT3-deficient hyper-IgE syndrome. Structural basis for STAT2 suppression by flavivirus NS5. MiR-125b participates in the occurrence of preeclampsia by regulating the migration and invasion of extravillous trophoblastic cells through STAT3 signaling pathway. Cancer-associated Fibroblasts induce epithelial-mesenchymal transition via the Transglutaminase 2-dependent IL-6/IL6R/STAT3 axis in Hepatocellular Carcinoma. The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis. Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3. LincRNA-Cox2 promotes pulmonary arterial hypertension by regulating the let-7a-mediated STAT3 signaling pathway. STAT3 Contributes to Intracranial Aneurysm Formation and Rupture by Modulating Inflammatory Response. STAT3 and GR Cooperate to Drive Gene Expression and Growth of Basal-Like Triple-Negative Breast Cancer. The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype. Interleukin-6 promotes proliferative vitreoretinopathy by inducing epithelial-mesenchymal transition via the JAK1/STAT3 signaling pathway. Activating mutations of STAT3: Impact on human growth. CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions. ApoC1 promotes the metastasis of clear cell renal cell carcinoma via activation of STAT3. Evaluation of STAT3 decoy oligodeoxynucleotides' synergistic effects on radiation and/or chemotherapy in metastatic breast cancer cell line. [Research progress on the role of STAT3 in cardiovascular diseases]. Insulin-like growth factor 1 promotes proliferation and invasion of papillary thyroid cancer through the STAT3 pathway. MicroRNA-29a functions as a tumor suppressor through targeting STAT3 in laryngeal squamous cell carcinoma. STAT3 as a predictive biomarker in head and neck cancer: A validation study. NOK associates with c-Src and promotes c-Src-induced STAT3 activation and cell proliferation. A role for annexin A2 in scaffolding the peroxiredoxin 2-STAT3 redox relay complex. Spontaneous Gastrointestinal Perforations in STAT3-Deficient Hyper-IgE Syndrome. STAT3 signaling pathway is involved in the pathogenesis of miscarriage. A novel STAT3 mutation associated with hyper immunoglobulin E syndrome with a paucity of connective tissue signs. Aryl hydrocarbon receptor mediates Jak2/STAT3 signaling for non-small cell lung cancer stem cell maintenance. Ruxolitinib Controls Lymphoproliferation and Diabetes in a STAT3-GOF Patient. Phosphorylation of STAT3 and ERBB2 mediates hypoxiainduced VEGF release in ARPE19 cells. RAD52 aptamer regulates DNA damage repair and STAT3 in BRCA1/BRCA2deficient human acute myeloid leukemia. STAT3 isoforms differentially affect ACE2 expression: A potential target for COVID-19 therapy. Systematic Transcriptional Profiling of Responses to STAT1- and STAT3-Activating Cytokines in Different Cancer Types. Lymphocytic Colitis With Increased Apoptosis: A Marker of Mutation in T-Cell-Mediated Immunity? CKS1B promotes cell proliferation and invasion by activating STAT3/PD-L1 and phosphorylation of Akt signaling in papillary thyroid carcinoma. MiR-944/CISH mediated inflammation via STAT3 is involved in oral cancer malignance by cigarette smoking. Dual PLK1 and STAT3 inhibition promotes glioblastoma cells apoptosis through MYC. Targeting STAT3 in Cancer Immunotherapy. Redox Regulation of STAT1 and STAT3 Signaling. [Expression of pSTAT3 and PD-L1 in extranodal NK/T cell lymphoma and its clinical significance]. Noncanonical pS727 post translational modification dictates major STAT3 activation and downstream functions in breast cancer. Autocrine Leukemia Inhibitory Factor Promotes Esophageal Squamous Cell Carcinoma Progression via Src Family Kinase-Dependent Yes-Associated Protein Activation. Loss of keratinocyte Mcpip1 abruptly activates the IL-23/Th17 and Stat3 pathways in skin inflammation. STAT3 gene polymorphism in chronic obstructive pulmonary disease. LncRNA MALAT1 Promotes STAT3-Mediated Endothelial Inflammation by Counteracting the Function of miR-590. STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells. TIMP-2 regulates proliferation, invasion and STAT3-mediated cancer stem cell-dependent chemoresistance in ovarian cancer cells. EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3. A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis. HMGB1 Recruits TET2/AID/TDG to Induce DNA Demethylation in STAT3 Promoter in CD4(+) T Cells from aGVHD Patients. Nobiletin inhibits viability of human renal carcinoma cells via the JAK2/STAT3 and PI3K/Akt pathway. STAT3 couples with 14-3-3sigma to regulate BCR signaling, B-cell differentiation, and IgE production. LRP8 activates STAT3 to induce PD-L1 expression in osteosarcoma. Two Cases With Features of Lymphocyte Variant Hypereosinophilic Syndrome With STAT3 SH2 Domain Mutations. LncRNA TSLNC8 synergizes with EGFR inhibitor osimertinib to inhibit lung cancer tumorigenesis by blocking the EGFR-STAT3 pathway. Clinicopathologic significance of MYD88 L265P mutation and expression of TLR4 and P-STAT3 in primary central nervous system diffuse large B-cell lymphomas. RNF180 mediates STAT3 activity by regulating the expression of RhoC via the proteasomal pathway in gastric cancer cells. Standardized Fraction of Turbinaria ornata Alleviates Dextran Sulfate Sodium-Induced Chronic Colitis in C57BL/6 Mice via Upregulation of FOXP3(+) Regulatory T Cells. Gremlin-1 activates Akt/STAT3 signaling, which increases the glycolysis rate in breast cancer cells. Leptin Downregulates Angulin-1 in Active Crohn's Disease via STAT3. Downregulation of N-myc Interactor Promotes Cervical Cancer Cells Growth by Activating Stat3 Signaling. LUCAT1 Epigenetically Downregulates the Tumor Suppressor Genes CXXC4 and SFRP2 in Gastric Cancer. IL-21 enhances STAT3/Blimp-1 signaling pathway in B cells and contributes to plasma cell differentiation in newly diagnosed patients with myasthenia gravis. STAT3 activation in HER2-positive breast cancers: Analysis of data from a large prospective trial. miR1243p regulates angiogenesis in peripheral arterial disease by targeting STAT3. Long noncoding RNA SNHG20 promotes colorectal cancer cell proliferation, migration and invasion via miR495/STAT3 axis. Colitis-induced IL11 promotes colon carcinogenesis. MicroRNA215p protects melanocytes via targeting STAT3 and modulating Treg/Teff balance to alleviate vitiligo. The cross-talk between STAT1/STAT3 and ROS up-regulates PD-L1 and promotes the release of pro-inflammatory/immune suppressive cytokines in primary monocytes infected by HHV-6B. Genomic characterization of HIV-associated plasmablastic lymphoma identifies pervasive mutations in the JAK-STAT pathway. STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in renal cell carcinoma. STAT3 enhances radiation-induced tumor migration, invasion and stem-like properties of bladder cancer. SphK1 promotes development of nonsmall cell lung cancer through activation of STAT3. Glutathione Stransferase omega 1 promotes the proliferation, migration and invasion, and inhibits the apoptosis of nonsmall cell lung cancer cells, via the JAK/STAT3 signaling pathway. STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma. Pathogenic effects of inhibition of mTORC1/STAT3 axis facilitates Staphylococcus aureus-induced pyroptosis in human macrophages. STAT3 phosphorylation at Ser727 and Tyr705 differentially regulates the EMT-MET switch and cancer metastasis. CD63 negatively regulates hepatocellular carcinoma development through suppression of inflammatory cytokine-induced STAT3 activation. Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression. Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-kappaB and STAT3. Autocrine IL-6/STAT3 signaling aids development of acquired drug resistance in Group 3 medulloblastoma. [Mechanism of Anti Apoptosis and Immune Evasion in Drug-Resistant Leukemia Cells Mediated by STAT3]. [Effect of MiR-29b-3p Targeting STAT3 on Proliferation and Apoptosis of Acute Myeloid Leukemia Cells]. Signal transducer and activator of transcription 3 mediates apoptosis inhibition through reducing mitochondrial ROS and activating Bcl-2 in gemcitabine-resistant lung cancer A549 cells. Pharmacological Inhibition of CDK8 in Triple-Negative Breast Cancer Cell Line MDA-MB-468 Increases E2F1 Protein, Induces Phosphorylation of STAT3 and Apoptosis. Recombinant Human IL-11 Promotes Lung Adenocarcinoma A549 Cell Growth and EMT through Activating STAT3/HIF-1alpha/EMT Signaling Pathway. hsa_circ_0006916 promotes hepatocellular carcinoma progression by activating the miR-337-3p/STAT3 axis. Clinicopathological and Prognostic Roles of STAT3 and Its Phosphorylation in Glioma. IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway. ANP32A promotes the proliferation, migration and invasion of hepatocellular carcinoma by modulating the HMGA1/STAT3 pathway. Epigenetic Silencing of Tumor Suppressor miR-124 Directly Supports STAT3 Activation in Cutaneous T-Cell Lymphoma. HPRT promotes proliferation and metastasis in head and neck squamous cell carcinoma through direct interaction with STAT3. Activation of the regeneration-associated gene STAT3 and functional changes in intact nociceptors after peripheral nerve damage in mice. CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci. MiR-3666 serves as a tumor suppressor in ovarian carcinoma by down-regulating AK4 via targeting STAT3. Epigenetic mechanisms shape the underlining expression regulatory mechanisms of the STAT3 in multiple sclerosis disease. IL-6/STAT3-mediated autophagy participates in the development of age-related glomerulosclerosis. An Unusual Pattern of Premature Cervical Spine Degeneration in STAT3-LOF. STAT3 and STAT5B mutations have unique distribution in T-cell large granular lymphocyte proliferations and advanced myeloid neoplasms. ROSmediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC. Targeting STAT3 by a small molecule suppresses pancreatic cancer progression. Life-Saving, Dose-Adjusted, Targeted Therapy in a Patient with a STAT3 Gain-of-Function Mutation. LncRNA ZFAS1 inhibits triple-negative breast cancer by targeting STAT3. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines. STAT3/miR-15a-5p/CX3CL1 Loop Regulates Proliferation and Migration of Vascular Endothelial Cells in Atherosclerosis. An Unexpected Infection in Loss-of-Function Mutations in STAT3: Malignant Alveolar Echinococcosis in Liver. Opioids drive breast cancer metastasis through the delta-opioid receptor and oncogenic STAT3. Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3. Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis. Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells. PKM2 promotes cell metastasis and inhibits autophagy via the JAK/STAT3 pathway in hepatocellular carcinoma. CREPT/RPRD1B promotes tumorigenesis through STAT3-driven gene transcription in a p300-dependent manner. A short deletion in the DNA-binding domain of STAT3 suppresses growth and progression of colon cancer cells. LncRNA LINC01116 sponges miR-93-5p to promote cell invasion and migration in small cell lung cancer. Stabilization of C/EBPbeta through direct interaction with STAT3 in H-Ras transformed human mammary epithelial cells. Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling. Mitochondrial STAT3 regulates antioxidant gene expression through complex I-derived NAD in triple negative breast cancer. MiR-29a Alleviates High Glucose-induced Inflammation and Mitochondrial Dysfunction via Modulation of IL-6/STAT3 in Diabetic Cataracts. RLIP depletion induces apoptosis associated with inhibition of JAK2/STAT3 signaling in melanoma cells. Overexpression of Stat3 increases circulating cfDNA in breast cancer. Milk fat globule EGF factor 8 restores mitochondrial function via integrin-medicated activation of the FAK-STAT3 signaling pathway in acute pancreatitis. SHP1 Decreases Level of P-STAT3 (Ser727) and Inhibits Proliferation and Migration of Pancreatic Cancer Cells. Quercetin Induces Apoptosis in Glioblastoma Cells by Suppressing Axl/IL-6/STAT3 Signaling Pathway. Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. The miR-19b-3p-MAP2K3-STAT3 feedback loop regulates cell proliferation and invasion in esophageal squamous cell carcinoma. d-Carvone inhibits the JAK/STAT3 signaling pathway and induced the apoptotic cell death in the human gastric cancer AGS cells. Distinct effects of V617F and exon12-mutated JAK2 expressions on erythropoiesis in a human induced pluripotent stem cell (iPSC)-based model. STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients. Contribution of STAT3 to the pathogenesis of COVID-19. Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3. Shikonin-mediated PD-L1 degradation suppresses immune evasion in pancreatic cancer by inhibiting NF-kappaB/STAT3 and NF-kappaB/CSN5 signaling pathways. STAT3 promotes peritoneal metastasis of gastric cancer by enhancing mesothelial-mesenchymal transition. Punicalagin induces ROS-mediated apoptotic cell death through inhibiting STAT3 translocation in lung cancer A549 cells. p-STAT3 expression in breast cancer correlates negatively with tumor size and HER2 status. NSD2 promotes tumor angiogenesis through methylating and activating STAT3 protein. LLL12B, a small molecule STAT3 inhibitor, induces growth arrest, apoptosis, and enhances cisplatin-mediated cytotoxicity in medulloblastoma cells. The subcellular redistribution of NLRC5 promotes angiogenesis via interacting with STAT3 in endothelial cells. Syringic acid regulates suppression of the STAT3/JNK/AKT pathway via inhibition of human ovarian teratoma cancer cell (PA-1) growth-in vitro study. miR320a3P alleviates the epithelialmesenchymal transition of A549 cells by activation of STAT3/SMAD3 signaling in a pulmonary fibrosis model. MLKL inhibits intestinal tumorigenesis by suppressing STAT3 signaling pathway. Propofol inhibited gastric cancer proliferation via the hsa-miR-328-3p/STAT3 pathway. Sequestration of the Transcription Factor STAT3 by the Molecular Chaperone CCT: A Potential Mechanism for Modulation of STAT3 Phosphorylation. STAT3 governs the HIF-1alpha response in IL-15 primed human NK cells. Ledipasvir/Sofosbuvir Eradicates Hepatitis C in an Immunodeficient STAT3-GOF Patient. SphK1 Promotes Cancer Progression through Activating JAK/STAT Pathway and Up-Regulating S1PR1 Expression in Colon Cancer Cells. Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation. hsa_circ_0001610 knockdown modulates miR-646-STAT3 axis to suppress endometrial carcinoma progression. Protein tyrosine phosphatase receptor type D gene promotes radiosensitivity via STAT3 dephosphorylation in nasopharyngeal carcinoma. Association between Single Nucleotide Polymorphism rs9891119 of STAT3 Gene and the Genetic Susceptibility to Type 2 Diabetes in Chinese Han Population from Guangdong. Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression. SH3BGRL3, transcribed by STAT3, facilitates glioblastoma tumorigenesis by activating STAT3 signaling. The STAT3 inhibitor Stattic acts independently of STAT3 to decrease histone acetylation and modulate gene expression. Long non-coding RNA LEISA promotes progression of lung adenocarcinoma via enhancing interaction between STAT3 and IL-6 promoter. Prothymosin alpha promotes colorectal carcinoma chemoresistance through inducing lipid droplet accumulation. Dimethyl fumarate induces ferroptosis and impairs NF-kappaB/STAT3 signaling in DLBCL. Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing. Methylomic analysis identifies C11orf87 as a novel epigenetic biomarker for GI cancers. microRNA-1246-containing extracellular vesicles from acute myeloid leukemia cells promote the survival of leukemia stem cells via the LRIG1-meditated STAT3 pathway. Circular RNA hsa_circ_0000117 accelerates the proliferation and invasion of gastric cancer cells by regulating the microRNA-337-3p/signal transducer and activator of transcription 3 axis. The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma. Signal transducer and activator of transcription 3 (STAT3) acts as a proviral factor for dengue virus propagation. KDM4B Overexpression Promotes the Growth, Migration, and Invasion of Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Activating STAT3 Pathway. A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin. IL-35 promotes EMT through STAT3 activation and induces MET by promoting M2 macrophage polarization in HCC. Electrophilic nitro-fatty acids suppress psoriasiform dermatitis: STAT3 inhibition as a contributory mechanism. Sorting nexin 3 induces heart failure via promoting retromer-dependent nuclear trafficking of STAT3. Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia. Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma. Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway. Periplogenin suppresses the growth of esophageal squamous cell carcinoma in vitro and in vivo by targeting STAT3. Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein-Barr virus-positive gastric cancer. Feed-forward activation of STAT3 signaling limits the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) treatment. PRMT5 Enables Robust STAT3 Activation via Arginine Symmetric Dimethylation of SMAD7. Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3. Novel STAT-3 gain-of-function variant with hypogammaglobulinemia and recurrent infection phenotype. Long non-coding RNA TINCR promotes hepatocellular carcinoma proliferation and invasion via STAT3 signaling by direct interacting with T-cell protein tyrosine phosphatase (TCPTP). STAT3 is over-activated within CD163(pos) bone marrow macrophages in both Multiple Myeloma and the benign pre-condition MGUS. STAT3 activation in thymic epithelial tumors: correlation with cyclin D1, JAK3, and clinical behavior. Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer. Activation of the STAT3 Signaling Pathway by the RNA-Dependent RNA Polymerase Protein of Arenavirus. STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation. Fat mass and obesity-associated protein (FTO) mediates signal transducer and activator of transcription 3 (STAT3)-drived resistance of breast cancer to doxorubicin. Cryptolepine inhibits hepatocellular carcinoma growth through inhibiting interleukin-6/STAT3 signalling. Reduction of serum-induced endothelial STAT3(Y705) activation is associated with preeclampsia. Myristoylation-mediated phase separation of EZH2 compartmentalizes STAT3 to promote lung cancer growth. A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance. Signal transducer and activator of transcription 3 as a potential therapeutic target for Graves' orbitopathy. Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance. Raddeanin A induced apoptosis of non-small cell lung cancer cells by promoting ROS-mediated STAT3 inactivation. TSLP-induced collagen type-I synthesis through STAT3 and PRMT1 is sensitive to calcitriol in human lung fibroblasts. SP2509, an inhibitor of LSD1, exerts potential antitumor effects by targeting the JAK/STAT3 signaling. Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child. RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation. [Targeted binding of rs1053005 locus of STAT3 with miR-452-3p and the association between STAT3 gene polymorphism and noise-induced hearing loss]. Long non-coding RNA LINC00511 regulates the expression of microRNA-625-5p and activates signal transducers and activators of transcription 3 (STAT3) to accelerate the progression of gastric cancer. Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion. STAT3-induced ZBED3-AS1 promotes the malignant phenotypes of melanoma cells by activating PI3K/AKT signaling pathway. Atiprimod triggered apoptotic cell death via acting on PERK/eIF2alpha/ATF4/CHOP and STAT3/NF-KappaB axis in MDA-MB-231 and MDA-MB-468 breast cancer cells. STAT3 polymorphisms in North Africa and its implication in breast cancer. circFAT1 Promotes Cancer Stemness and Immune Evasion by Promoting STAT3 Activation. Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling. Genetics and Functional Mechanisms of STAT3 Polymorphisms in Human Tuberculosis. CLEC12B Decreases Melanoma Proliferation by Repressing Signal Transducer and Activator of Transcription 3. Curcumol may alleviate psoriasis-like inflammation by inhibiting keratinocyte proliferation and inflammatory gene expression via JAK1/STAT3 signaling. The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation. miR-526b-3p inhibits lung cancer cisplatin-resistance and metastasis by inhibiting STAT3-promoted PD-L1. USP24-GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway. STAT3 mediated upregulation of C-MET signaling acts as a compensatory survival mechanism upon EGFR family inhibition in chemoresistant breast cancer cells. Germline STAT3 gain-of-function mutations in primary immunodeficiency: Impact on the cellular and clinical phenotype. MicroRNA-4458 Regulates PD-L1 Expression to Enhance Anti-tumor Immunity in NSCLC via Targeting STAT3. Phenotypes of STAT3 gain-of-function variant related to disruptive regulation of CXCL8/STAT3, KIT/STAT3, and IL-2/CD25/Treg axes. Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus. PI3K-AKT, JAK2-STAT3 pathways and cell-cell contact regulate maspin subcellular localization. Cucurbitacin B enhances apoptosis in gefitinib resistant nonsmall cell lung cancer by modulating the miR175p/STAT3 axis. STAT3/LINC00671 axis regulates papillary thyroid tumor growth and metastasis via LDHA-mediated glycolysis. The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling. PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3. Acute myeloid leukemia cell-derived extracellular vesicles carrying microRNA-548ac regulate hematopoietic function via the TRIM28/STAT3 pathway. SHOX2 cooperates with STAT3 to promote breast cancer metastasis through the transcriptional activation of WASF3. Circ-E2F3 promotes cervical cancer progression by inhibiting microRNA-296-5p and increasing STAT3 nuclear translocation. A Potential ceRNA Network for Neurological Damage in Preterm Infants. SLCO1B3 promotes colorectal cancer tumorigenesis and metastasis through STAT3. The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling. Circular RNA-0007059 protects cell viability and reduces inflammation in a nephritis cell model by inhibiting microRNA-1278/SHP-1/STAT3 signaling. FTO Suppresses STAT3 Activation and Modulates Proinflammatory Interferon-Stimulated Gene Expression. Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling. SPHK1 contributes to cisplatin resistance in bladder cancer cells via the NONO/STAT3 axis. Early-onset, fatal interstitial lung disease in STAT3 gain-of-function patients. SIGIRR Mutation in Human Necrotizing Enterocolitis (NEC) Disrupts STAT3-Dependent microRNA Expression in Neonatal Gut. STAT3beta disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma. Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells. Selenium sulfide disrupts the PLAGL2/C-MET/STAT3-induced resistance against mitochondrial apoptosis in hepatocellular carcinoma. Macrophage/microglia-derived IL-1beta induces glioblastoma growth via the STAT3/NF-kappaB pathway. SAA1 is transcriptionally activated by STAT3 and accelerates renal interstitial fibrosis by inducing endoplasmic reticulum stress. STAT3-Specific Single Domain Nanobody Inhibits Expansion of Pathogenic Th17 Responses and Suppresses Uveitis in Mice. Circular RNA UBE2Q2 promotes malignant progression of gastric cancer by regulating signal transducer and activator of transcription 3-mediated autophagy and glycolysis. Chaperonin containing TCP1 subunit 3 (CCT3) promotes cisplatin resistance of lung adenocarcinoma cells through targeting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway. TRIM59 promotes osteosarcoma progression via activation of STAT3. Activation of STAT3 signaling pathway in the kidney of COVID-19 patients. Discovery of Novel Polycyclic Polyprenylated Acylphloroglucinols from the Fruits of Garcinia xanthochymus as Antitumor Agents by Suppressing the STAT3 Signaling. Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function. NEK6 is an injury-responsive kinase cooperating with STAT3 in regulation of reactive astrogliosis. STAT3 Gain-of-Function Mutations Underlie Deficiency in Human Nonclassical CD16(+) Monocytes and CD141(+) Dendritic Cells. STAT3 mediated regulation of glucose metabolism in leukemia cells. Knockdown of long noncoding RNA AC245100.4 inhibits the tumorigenesis of prostate cancer cells via the STAT3/NR4A3 axis. EGFR transcriptionally upregulates UTX via STAT3 in non-small cell lung cancer. CD11c+CD163+ Cells and Signal Transducer and Activator of Transcription 3 (STAT3) Expression Are Common in Melanoma Leptomeningeal Disease. CRY1 Regulates Chemoresistance in Association With NANOG by Inhibiting Apoptosis via STAT3 Pathway in Patients With Cervical Cancer. Somatic STAT3 mutations in CD8(+) T cells of healthy blood donors carrying human T-cell leukemia virus type 2. Silencing of ISLR inhibits tumour progression and glycolysis by inactivating the IL6/JAK/STAT3 pathway in nonsmall cell lung cancer. Eriocitrin, a dietary flavonoid suppressed cell proliferation, induced apoptosis through modulation of JAK2/STAT3 and JNK/p38 MAPKs signaling pathway in MCF-7 cells. p-STAT3 is a PDC-E2 interacting partner in human cholangiocytes and hepatocytes with potential pathobiological implications. Dihydroartemisinin inhibits IL-6-induced epithelial-mesenchymal transition in laryngeal squamous cell carcinoma via the miR-130b-3p/STAT3/beta-catenin signaling pathway. Inside-out and outside-in organotypic normal human skin culture: JAK-STAT pathway is activated after pro-inflammatory psoriatic cytokine exposure. Nucleostemin upregulation and STAT3 activation as early events in oral epithelial dysplasia progression to squamous cell carcinoma. Evaluation of selected IL6/STAT3 pathway molecules and miRNA expression in chronic obstructive pulmonary disease. Tumor-Derived Small Extracellular Vesicles Induce Pro-Inflammatory Cytokine Expression and PD-L1 Regulation in M0 Macrophages via IL-6/STAT3 and TLR4 Signaling Pathways. Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway. 5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT, and ERK Activity. CircZNF532 knockdown protects retinal pigment epithelial cells against high glucose-induced apoptosis and pyroptosis by regulating the miR-20b-5p/STAT3 axis. STAT3-induced NCK1 elevation promotes migration of triple-negative breast cancer cells via regulating ERK1/2 signaling. Targeting STAT3 prevents bile reflux-induced oncogenic molecular events linked to hypopharyngeal carcinogenesis. Exploiting the STAT3 Nexus in Cancer-Associated Fibroblasts to Improve Cancer Therapy. miR-181a is a novel player in the STAT3-mediated survival network of TCRalphabeta+ CD8+ T large granular lymphocyte leukemia. CD8+ cell somatic mutations in multiple sclerosis patients and controls-Enrichment of mutations in STAT3 and other genes implicated in hematological malignancies. Aloperine inhibits colorectal cancer cell proliferation and metastasis progress via regulating miR-296-5p/STAT3 axis. Opposing Effects of Chelidonine on Tyrosine and Serine Phosphorylation of STAT3 in Human Uveal Melanoma Cells. Tomato and Olive Bioactive Compounds: A Natural Shield against the Cellular Effects Induced by beta-Hexachlorocyclohexane-Activated Signaling Pathways. Effects of Interleukin-6 on STAT3-regulated signaling in oral cancer and as a prognosticator of patient survival. Role of STAT3 Transcription Factor in Pathogenesis of Bronchial Asthma. STAT3 Promotes Cell Proliferation by Potentiating the CCL4 Transcriptional Activity in Diffuse Large B-Cell Lymphoma. PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD. Diffuse large B-cell lymphoma-derived exosomes push macrophage polarization toward M2 phenotype via GP130/STAT3 signaling pathway. Thrombospondin-1 induced programmed death-ligand 1-mediated immunosuppression by activating the STAT3 pathway in osteosarcoma. Serum JAK/STAT profile is related to the IL expression but not with the outcome in pancreatic adenocarcinoma patients. Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-kappaB Signaling Pathways by Natural Compounds. KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3. STAT3 Polymorphism Associates With mTOR Inhibitor-Induced Interstitial Lung Disease in Patients With Renal Cell Carcinoma. Arsenic activates STAT3 signaling during the transformation of the human bronchial epithelial cells. The critical role of STAT3 in biogenesis of tumor-derived exosomes with potency of inducing cancer cachexia in vitro and in vivo. STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts. E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity. TSLP Impairs Epidermal Barrier Integrity by Stimulating the Formation of Nuclear IL-33/Phosphorylated STAT3 Complex in Human Keratinocytes. STAT3 and SPI1, may lead to the immune system dysregulation and heterotopic ossification in ankylosing spondylitis. STAT3-regulated LncRNA LINC00160 mediates cell proliferation and cell metabolism of prostate cancer cells by repressing RCAN1 expression. STAT3/HIF1A and EMT specific transcription factors regulated genes: Novel predictors of breast cancer metastasis. NCAPD3 promotes prostate cancer progression by up-regulating EZH2 and MALAT1 through STAT3 and E2F1. High Dimensional Analyses of Circulating Immune Cells in Psoriatic Arthritis Detects Elevated Phosphorylated STAT3. Circ_0001947 promotes cell proliferation, invasion, migration and inflammation and inhibits apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes through miR-671-5p/STAT3 axis. MAL protein suppresses the metastasis and invasion of GC cells by interfering with the phosphorylation of STAT3. Gallbladder Cancer Cell-Derived Exosome-Mediated Transfer of Leptin Promotes Cell Invasion and Migration by Modulating STAT3-Mediated M2 Macrophage Polarization. ZNF32 promotes the self-renewal of colorectal cancer cells by regulating the LEPR-STAT3 signaling pathway. Novel STAG3 variant associated with primary ovarian insufficiency and non-obstructive azoospermia in an Iranian consanguineous family. Atypical patterns of STAT3 phosphorylation in subpopulations B cells in patients with common variable immunodeficiency. [Associations between gene polymorphisms of signal transducer and activator of transcription 3 and the susceptibility to hepatitis B virus related liver cirrhosis]. STAT3-mediated allelic imbalance of novel genetic variant Rs1047643 and B-cell-specific super-enhancer in association with systemic lupus erythematosus. ALDH3A1 overexpression in OSCC inhibits inflammation via phospho-Ser727 at STAT3 in tumor-associated macrophages. Overexpression of GSTP1 promotes colorectal cancer cell proliferation, invasion and metastasis by upregulating STAT3. EGFR signaling promotes nuclear translocation of plasma membrane protein TSPAN8 to enhance tumor progression via STAT3-mediated transcription. Identification of serum and glucocorticoid-regulated kinase 1 as a regulator of signal transducer and activator of transcription 3 signaling. Ginsenoside Rh4 Suppressed Metastasis of Lung Adenocarcinoma via Inhibiting JAK2/STAT3 Signaling. Matrine protects colon mucosal epithelial cells against inflammation and apoptosis via the Janus kinase 2 /signal transducer and activator of transcription 3 pathway. Nuclear expression of pSTAT3(Tyr705) and pSTAT3(Ser727) in the stromal compartment of localized hormone-naive prostate cancer. C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 7(CXCR7) regulates epithelial-mesenchymal transition process and promotes the metastasis of esophageal cancer by activating signal transducer and activator of transcription 3 (ST [...] T cell clonal expansion and STAT3 mutations: a characteristic feature of acquired chronic T cell-mediated pure red cell aplasia. Curcumol Attenuates Endometriosis by Inhibiting the JAK2/STAT3 Signaling Pathway. CircEIF5 contributes to hyperproliferation and inflammation of keratinocytes in psoriasis via p-NFkappaB and p-STAT3 signalling pathway. Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway. LncRNA RPSAP52 promotes cell proliferation and inhibits cell apoptosis via modulating miR-665/STAT3 in gastric cancer. Genome-Wide ChIP-seq and RNA-seq Analyses of STAT3 Target Genes in TLRs Activated Human Peripheral Blood B Cells. Molecular Mechanisms Driving IL-10- Producing B Cells Functions: STAT3 and c-MAF as Underestimated Central Key Regulators? STAT3, VEGF, and PSMA Expression Patterns in Malignant Peripheral Nerve Sheath Tumors, Malignant Melanomas, and Glioblastomas: Does Staining Percentage and Intensity Have an Effect on Survival? Constant Activation of STAT3 Contributes to the Development of Adenomyosis in Females. Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells. Exosomal PD-L1 confers chemoresistance and promotes tumorigenic properties in esophageal cancer cells via upregulating STAT3/miR-21. Glucose Increases STAT3 Activation, Promoting Sustained XRCC1 Expression and Increasing DNA Repair. Luteolin binds Src, promotes STAT3 protein ubiquitination and exerts anti-melanoma effects in cell and mouse models. ALKBH5 regulates STAT3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6A-YTHDF2-dependent manner. Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations. Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations. Growth differentiation factor 11 induces skeletal muscle atrophy via a STAT3-dependent mechanism in pulmonary arterial hypertension. Circ_0000274 contributes to renal cell carcinoma progression by regulating miR-338-3p/NUCB2 axis and JAK1/STAT3 pathway. Induction of Fibroblast Growth Factor Receptor 4 by Helicobacter pylori via Signal Transducer and Activator of Transcription 3 With a Feedforward Activation Loop Involving Steroid Receptor Coactivator Signaling in Gastric Cancer. Silencing GOLGA8B inhibits cell invasion and metastasis by suppressing STAT3 signaling pathway in lung squamous cell carcinoma. SPP1 promotes radiation resistance through JAK2/STAT3 pathway in esophageal carcinoma. STAT3 Activates the Pentraxin 3 Gene in Chronic Lymphocytic Leukemia Cells. GLI1 activates pro-fibrotic pathways in myelofibrosis fibrocytes. Inhibition of STAT3 enhances UCP1 expression and mitochondrial function in brown adipocytes. [The IL-6/STAT3 signaling pathway mediated by radiotherapy regulates the expression of PD-L1 in esophageal cancer cells]. STAT3 suppresses the AMPKalpha/ULK1-dependent induction of autophagy in glioblastoma cells. The minor allele of rs17427875 in long non-coding RNA-HOXA11-AS influences the prognosis of subarachnoid hemorrhage (SAH) via modulating miR-15a and STAT3 expression. STAT3 in medulloblastoma: a key transcriptional regulator and potential therapeutic target. Cryptococcus neoformans Infection Induces IL-17 Production by Promoting STAT3 Phosphorylation in CD4(+) T Cells. STAT3-confusion-of-function: Beyond the loss and gain dualism. Circ-HSP90A expedites cell growth, stemness, and immune evasion in non-small cell lung cancer by regulating STAT3 signaling and PD-1/PD-L1 checkpoint. Evaluation of the putative lymphoma-associated point mutation D427H in the STAT3 transcription factor. TRIM27-USP7 complex promotes tumour progression via STAT3 activation in human hepatocellular carcinoma. IL-17 Induces Autophagy Dysfunction to Promote Inflammatory Cell Death and Fibrosis in Keloid Fibroblasts via the STAT3 and HIF-1alpha Dependent Signaling Pathways. The Impact of STAT3 rs1053005 Variation on Type 1 Diabetes Mellitus Susceptibility: Association Study and in Silico Analysis. IL-6 activates pathologic Th17 cell via STAT 3 phosphorylation in inflammatory joint of Ankylosing Spondylitis. EZH2 Promotes T Follicular Helper Cell Differentiation Through Enhancing STAT3 Phosphorylation in Patients With Primary Sjogren's Syndrome. Tetrandrine-induced downregulation of lncRNA NEAT1 inhibits rheumatoid arthritis progression through the STAT3/miR-17-5p pathway. Expression of mycobacterium tuberculosis induced SOCS3 and STAT3 and the implications on innate immunity in TB patients vs healthy contacts in high TB/HIV endemic setting: A cross-sectional analytical study. SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization. Prognostic significance of STAT3 gene expression in patients with glioblastoma tumors: a study from Western India. The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma. LncRNA CASC9 activated by STAT3 promotes the invasion of breast cancer and the formation of lymphatic vessels by enhancing H3K27ac-activated SOX4. The Multifaceted Role of STAT3 in NK-Cell Tumor Surveillance. CXCL1 confers a survival advantage in Kaposi's sarcoma-associated herpesvirus-infected human endothelial cells through STAT3 phosphorylation. ARPC1A is regulated by STAT3 to inhibit ferroptosis and promote prostate cancer progression. STAT3-mediated osteogenesis and osteoclastogenesis in osteoporosis. Hepatokine Fetuin B expression is regulated by leptin-STAT3 signalling and associated with leptin in obesity. STAT3 gain-of-function is not responsible for low total IgE levels in patients with autoimmune chronic spontaneous urticaria. Pinus mugo Essential Oil Impairs STAT3 Activation through Oxidative Stress and Induces Apoptosis in Prostate Cancer Cells. Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer. Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer. MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis. PDGFRbeta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma. Analysis of CF patient survival confirms STAT3 as a CF-modifying gene with changing impact over time. STAT3 and PD-L1 are negatively correlated with ATM and have impact on the prognosis of triple-negative breast cancer patients with low ATM expression. MicroRNA-29b regulates pyroptosis involving calcific aortic valve disease through the STAT3/SOCS1 pathway. Leptin Promotes Angiogenesis via Pericyte STAT3 Pathway upon Intracerebral Hemorrhage. Downregulation of miR-125a-5p Leads to STAT3 Increased Expression in Breast Cancer Patients. Modulation of SOCS3 Levels via STAT3 and Estrogen-ERalphap66 Signaling during Hepatitis E Virus Replication in Hepatocellular Carcinoma Cells. Inhibition of O-GlcNAcase Inhibits Hematopoietic and Leukemic Stem Cell Self-Renewal and Drives Dendritic Cell Differentiation via STAT3/5 Signaling. A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice. TIPE1 inhibits osteosarcoma tumorigenesis and progression by regulating PRMT1 mediated STAT3 arginine methylation. NINJ1 triggers extravillous trophoblast cell dysfunction through blocking the STAT3 signaling pathway. Role of STAT3 in the initiation, progression, proliferation and metastasis of breast cancer and strategies to deliver JAK and STAT3 inhibitors. STAT-3 signaling role in an experimental model of nephropathy induced by doxorubicin. Overexpression of estrogen receptor beta inhibits cellular functions of human hepatic stellate cells and promotes the anti-fibrosis effect of calycosin via inhibiting STAT3 phosphorylation. STAT3 is Activated by CTGF-mediated Tumor-stroma Cross Talk to Promote HCC Progression. STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth. Ezh2[Y641F] mutations co-operate with Stat3 to regulate MHC class I antigen processing and alter the tumor immune response in melanoma. Clinicopathological Significance of STAT3 and p-STAT3 among 91 Patients with Adenocarcinoma of the Esophagogastric Junction. SENP3 affects the expression of PYCR1 to promote bladder cancer proliferation and EMT transformation by deSUMOylation of STAT3. Activation of STAT3 (signal transducer and activator of transcription 3) in synovial tissues from the hip joint in the early stage of rapidly destructive coxopathy. TRIB3 Interacts with STAT3 to Promote Cancer Angiogenesis. Crosstalk between heat shock factor 1 and signal transducer and activator of transcription 3 mediated by interleukin-8 autocrine signaling maintains the cancer stem cell phenotype in liver cancer. IL-6/Stat3 suppresses osteogenic differentiation in ossification of the posterior longitudinal ligament via miR-135b-mediated BMPER reduction. Osteoprotegerin (OPG) Upregulation Activates Breast Stromal Fibroblasts and Enhances Their Pro-Carcinogenic Effects through the STAT3/IL-6 Signaling. Adiponectin Suppresses Metastasis of Nasopharyngeal Carcinoma through Blocking the Activation of NF-kappaB and STAT3 Signaling. ENO1 Binds to ApoC3 and Impairs the Proliferation of T Cells via IL-8/STAT3 Pathway in OSCC. Osteoblastic STAT3 Is Crucial for Orthodontic Force Driving Alveolar Bone Remodeling and Tooth Movement. Exosome-transmitted S100A4 induces immunosuppression and non-small cell lung cancer development by activating STAT3. Extracellular vesicles from focal segmental glomerulosclerosis pediatric patients induce STAT3 activation and mesangial cell proliferation. Programmed death ligand 1 intracellular interactions with STAT3 and focal adhesion protein Paxillin facilitate lymphatic endothelial cell remodeling. APC/C CDH1 ubiquitinates STAT3 in mitosis. The signal transducer and activator of transcription 3 at the center of the causative gene network of the hyper-IgE syndrome. MiRNA-374b-5p and miRNA-106a-5p are related to inflammatory bowel disease via regulating IL-10 and STAT3 signaling pathways. High prevalence of low-allele-fraction somatic mutations in STAT3 in peripheral blood CD8+ cells in multiple sclerosis patients and controls. STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2D[hi] CD8[+] T cell dysregulation and accumulation. JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models. Expression of p-STAT3 and c-Myc correlates with P2-HNF4alpha expression in nonalcoholic fatty liver disease (NAFLD). Increased expression of the p-STAT3/IL-17 signaling pathway in patients with dermatomyositis. STAT3 suppression and beta-cell ablation enhance alpha-to-beta reprogramming mediated by Pdx1. STAT3 expression in patients with fragility fractures and its effect on the biological function of osteoblasts. STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression. Allosteric regulation in STAT3 interdomains is mediated by a rigid core: SH2 domain regulation by CCD in D170A variant. Transcription Factors STAT3 and MYC Are Key Players of Human Platelet Lysate-Induced Cell Proliferation. Highly expressed FYN promotes the progression of placenta accreta by activating STAT3, p38, and JNK signaling pathways. Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience. SBNO2 is a critical mediator of STAT3-driven hematological malignancies. STAT3 promotes a youthful epigenetic state in articular chondrocytes. STAT3 mutation-associated airway epithelial defects in Job syndrome. Importance of STAT3 Polymorphisms on the Risk and Clinical Characteristics of Rheumatoid Arthritis. The ups and downs of STAT3 function: too much, too little and human immune dysregulation. STAT3 promotes RNA polymerase III-directed transcription by controlling the miR-106a-5p/TP73 axis. A bio-orthogonal linear ubiquitin probe identifies STAT3 as a direct substrate of OTULIN in glioblastoma. STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection. Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop. STAT3 regulation of Mtb-specific T cell function in active pulmonary tuberculosis patients. LAPTM4B promotes AML progression through regulating RPS9/STAT3 axis. The research development of STAT3 in hepatic ischemia-reperfusion injury. Multi-Omics Profiling in PGM3 and STAT3 Deficiencies: A Tale of Two Patients. GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation. An HLA-G/SPAG9/STAT3 axis promotes brain metastases. The positive feedback loop of MAD2L1/TYK2/STAT3 induces progression in B-cell acute lymphoblastic leukaemia. STAT3 regulates 5-Fu resistance in human colorectal cancer cells by promoting Mcl-1-dependent cytoprotective autophagy. pSTAT3 influences doxorubicin and etoposide resistance of A549 cells grown in an in vitro 3D culture model. Redox-Dependent Activation of Lung Epithelial STAT3 Is Required for Inducible Protection against Bacterial Pneumonia. Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia. RANKL Promotes Chemotherapy Resistance in Breast Cancer Cells Through STAT3 Mediated Autophagy Induction. LincRNA00612 inhibits apoptosis and inflammation in LPS-induced BEAS-2B cells via enhancing interaction between p-STAT3 and A2M promoter. Rabeprazole destroyed gastric epithelial barrier function through FOXF1/STAT3-mediated ZO-1 expression. STAT3 signaling in prostate cancer progression and therapy resistance: An oncogenic pathway with diverse functions. Long Non-Coding RNA-GDA-1 Promotes Keratinocyte Proliferation and Psoriasis Inflammation by Regulating the STAT3/NF-kappaB Signaling Pathway via Forkhead Box M1. Association of STAT3, CYP3A5, and ABCG2 Polymorphisms With Osimertinib-induced Adverse Events in NSCLC Patients. Comprehensive pan-cancer analysis of STAT3 as a prognostic and immunological biomarker. NF-kappaB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer. Cold plasma and inhibition of STAT3 selectively target tumorigenicity in osteosarcoma. CircRPPH1 accelerates the proliferation and migration of bladder cancer via enhancing the STAT3 signaling pathway. The inflammatory macrophages repress the growth of bone metastatic human prostate cancer cells via TNF-alpha and IL-6 signaling: Involvement of cell signaling regulator regucalcin. STAT3 signaling in pancreatic ductal adenocarcinoma: a candidate therapeutic target. RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status. Protein Kinase CK2 Promotes Proliferation, Abnormal Differentiation, and Proinflammatory Cytokine Production of Keratinocytes via Regulation of STAT3 and Akt Pathways in Psoriasis. Advances in the role of STAT3 in macrophage polarization. Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance. Differential silencing of STAT3 isoforms leads to changes in STAT3 activation. Apoptosis of pro-B lymphocytes induced by NR4A1 activation in the presence of gingival fibroblast exosomes and TNFalpha, caspase 8, STAT3, and Akt pathways modulators. New Ways to Protect the Host from SARS-CoV-2? Lung Microbiome Metabolites Inhibit STAT3 and Modulate the Immunological Network. The LINC00501-HSP90B1-STAT3 positive feedback loop promotes malignant behavior in gastric cancer cells. LCN2 Promotes Proliferation and Glycolysis by Activating the JAK2/STAT3 Signaling Pathway in Hepatocellular Carcinoma. High expression of STAT3 within the tumour-associated stroma predicts poor outcome in breast cancer patients. [Signal transducer and activator of transcription 3 and cancer associated fibroblasts jointly generate chemo-resistance and affect prognosis in epithelial ovarian cancer]. SHP-1 alleviates atrial fibrosis in atrial fibrillation by modulating STAT3 activation. METTL3 and STAT3 form a positive feedback loop to promote cell metastasis in hepatocellular carcinoma. Mesenchymal stem cells-derived IL-6 promotes invasion and metastasis of oral squamous cell carcinoma via JAK-STAT3 signalling. IL-6-Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis. TROAP Promotes the Proliferation, Migration, and Metastasis of Kidney Renal Clear Cell Carcinoma with the Help of STAT3. Endothelial Stat3 activation promotes osteoarthritis development. Reversible promoter demethylation of PDGFD confers gemcitabine resistance through STAT3 activation and RRM1 upregulation. AKAP12 promotes cancer stem cell-like phenotypes and activates STAT3 in colorectal cancer. The pulmonary effects of STAT3 deficiency. ROR1/STAT3 positive feedback loop facilitates cartilage degeneration in Osteoarthritis through activation of NF-kappaB signaling pathway. Dual inhibition of STAT3 and STAT5 may overcome imatinib resistance in chronic myeloid leukemia. STAT3 as a newly emerging target in colorectal cancer therapy: Tumorigenesis, therapy response, and pharmacological/nanoplatform strategies. JAK/STAT3 pathway promotes proliferation of ovarian aggregate-derived stem cells in vitro. TSLP/TSLPR promotes renal fibrosis by activating STAT3 in renal fibroblasts. RP11-296E3.2 acts as an important molecular chaperone for YBX1 and promotes colorectal cancer proliferation and metastasis by activating STAT3. Phosphorylated STAT3 as a potential diagnostic and predictive biomarker in ALK[-] ALCL vs. CD30[high] PTCL, NOS. Blockade of IL-11 Trans-Signaling or JAK2/STAT3 Signaling Ameliorates the Profibrotic Effect of IL-11. m[6] A reader YTHDF3 triggers the progression of hepatocellular carcinoma through the YTHDF3/m[6] A-EGFR/STAT3 axis and EMT. Vasorin promotes proliferation and migration via STAT3 signaling and acts as a promising therapeutic target of hepatocellular carcinoma. DBF4 Dependent Kinase Inhibition Suppresses Hepatocellular Carcinoma Progression and Potentiates Anti-Programmed Cell Death-1 Therapy. Prevalence of STAT3 mutations in patients with rheumatoid arthritis-associated T-cell large granular lymphocytic leukaemia and Felty syndrome. NFE2L2 and STAT3 Converge on Common Targets to Promote Survival of Primary Lymphoma Cells. Physical interaction between STAT3 and AP1 in cervical carcinogenesis: Implications in HPV transcription control. FTO promotes proliferation and migration of bladder cancer via enhancing stability of STAT3 mRNA in an m6A-dependent manner. Inhibition of BACE1 attenuates microglia-induced neuroinflammation after intracerebral hemorrhage by suppressing STAT3 activation. Classification of IDH wild-type glioblastoma tumorspheres into low- and high-invasion groups based on their transcriptional program. ANXA1 Promotes Tumor Immune Evasion by Binding PARP1 and Upregulating Stat3-Induced Expression of PD-L1 in Multiple Cancers. High Epstein-Barr virus capsid antigen IgG level associates with the carriership of CD8+ T cell somatic mutations in the STAT3 SH2 domain. Overexpression of SOCS2 Inhibits EMT and M2 Macrophage Polarization in Cervical Cancer via IL-6/JAK2/STAT3 Pathway. Influenza a virus regulates interferon signaling and its associated genes; MxA and STAT3 by cellular miR-141 to ensure viral replication. Increased serum alpha-tocopherol acetate mediated by gut microbiota ameliorates alveolar bone loss through the STAT3 signalling pathway in diabetic periodontitis. Reduced DEFA5 Expression and STAT3 Activation Underlie the Submucosal Invasion of Early Gastric Cancers. Perspective: mitochondrial STAT3 in cardioprotection. Genetic Association between Inflammatory-Related Polymorphism in STAT3, IL-1beta, IL-6, TNF-alpha and Idiopathic Recurrent Implantation Failure. TRIM14 Overexpression Induces Chemoresistance and Malignant Behaviors of Hepatocellular Carcinoma Cells by Activating the STAT3/HIF-1alpha Pathway. Targeting EZH2 regulates the biological characteristics of glioma stem cells via the Notch1 pathway. Shock drives a STAT3 and JunB-mediated coordinated transcriptional and DNA methylation response in the endothelium. alpha5-nAChR/STAT3/CD47 axis contributed to nicotine-related lung adenocarcinoma progression and immune escape. Synergistic effects of BTN3A1, SHP2, CD274, and STAT3 gene polymorphisms on the risk of systemic lupus erythematosus: a multifactorial dimensional reduction analysis. A STAT3 protein complex required for mitochondrial mRNA stability and cancer. PIK3R6 Promotes Angiogenesis in Hepatocellular carcinoma by Activating STAT3 Signaling Pathway. STAT3-EphA7 axis contributes to the progression of esophageal squamous cell carcinoma. Melatonin attenuates cellular senescence and apoptosis in diabetic nephropathy by regulating STAT3 phosphorylation. E3 Ubiquitin Ligase MARCH8 Promotes Pancreatic Cancer Growth and Metastasis by Activating STAT3 via Degradation of PTPN4. NF-kappaB and STAT3 activation in CD4 T cells in pediatric MOG antibody-associated disease. Possible Role of IL-6R/STAT3/MiRNA-34a Feedback Loop in Osteosarcoma. STAT3 promotes migration and invasion of cholangiocarcinoma arising from choledochal cyst by transcriptionally inhibiting miR200c through the c-myb/MEK/ERK signaling pathway. PRMT6 methylation of STAT3 regulates tumor metastasis in breast cancer. Sequential inspiratory muscle exercise-noninvasive positive pressure ventilation alleviates oxidative stress in COPD by mediating SOCS5/JAK2/STAT3 pathway. The Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Breast Cancer Are Regulated by N-Linked Glycosylation-Dependent Activation of STAT3 and STAT1. NMI promotes tumor progression and gemcitabine resistance in pancreatic cancer via STAT3-IFIT3 axis. KIF2C promotes clear cell renal cell carcinoma progression via activating JAK2/STAT3 signaling pathway. Expression profiling of signal transducer and activator of transcription3 in oral squamous cell carcinoma in south Indian population. Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay. USP7 promotes decidualization of ESCs by STAT3/PR axis during early pregnancy. RARgamma promotes the invasion and metastasis of thyroid carcinoma by activating the JAK1-STAT3-CD24/MMPs axis. TTC13 expression and STAT3 activation may form a positive feedback loop to promote ccRCC progression. GREM1 knockdown regulates the proliferation, apoptosis and EMT of benign prostatic hyperplasia by suppressing the STAT3/c-Myc signaling. LUCAT1 inhibits ferroptosis in bladder cancer by regulating the mRNA stability of STAT3. STAT3 phosphorylation at serine 727 activates specific genetic programs and promotes clear cell renal cell carcinoma (ccRCC) aggressiveness. VPS35 promotes gastric cancer progression through integrin/FAK/SRC signalling-mediated IL-6/STAT3 pathway activation in a YAP-dependent manner. Extracellular vesicle-encapsulated microRNA-296-3p from cancer-associated fibroblasts promotes ovarian cancer development through regulation of the PTEN/AKT and SOCS6/STAT3 pathways. Different phenotypes caused by a STAT3 variant in a Chinese pedigree. Direct and biologically significant interactions of human herpesvirus 8 interferon regulatory factor 1 with STAT3 and Janus kinase TYK2. Role of HDAC6-STAT3 in immunomodulatory pathways in Colorectal cancer cells. The acetylation of STAT3 at K685 attenuates NPM-ALK-induced tumorigenesis. ZNF70 regulates IL-1beta secretion of macrophages to promote the proliferation of HCT116 cells via activation of NLRP3 inflammasome and STAT3 pathway in colitis-associated colorectal cancer. METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway. STAT3 Signalling Drives LDH Up-Regulation and Adiponectin Down-Regulation in Cachectic Adipocytes. Hsa_circ_0013561 promotes progression of nasopharyngeal carcinoma by activating JAK2/STAT3 signaling pathway. Revisiting the role of endogenous STAT3 in HPV-positive cervical cancer cells. A novel axis of circKIF4A-miR-637-STAT3 promotes brain metastasis in triple-negative breast cancer. Prevention of STAT3-related pathway in SK-N-SH cells by natural product astaxanthin. STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice. Regulation of the STAT3 pathway by lupus susceptibility gene Pbx1 in T cells. Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population. CD44s and CD44v8-10 isoforms confer acquired resistance to osimertinib by activating the ErbB3/STAT3 signaling pathway. OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3. ITGA2 as a prognostic factor of glioma promotes GSCs invasion and EMT by activating STAT3 phosphorylation. ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3. Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor. PCSK9 regulates myofibroblast transformation through the JAK2/STAT3 pathway to regulate fibrosis after myocardial infarction. miR-26a-5p restoration via EZH2 silencing blocks the IL-6/STAT3 axis to repress the growth of prostate cancer. Circ_MAPK9 promotes STAT3 and LDHA expression by silencing miR-642b-3p and affects the progression of hepatocellular carcinoma. NCAPG2 promotes prostate cancer malignancy and stemness via STAT3/c-MYC signaling. VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms. Activation of HDAC8 Can Suppress the Proliferation of Osteosarcoma Cells via TP53 and STAT3/ERK Signaling Pathways. Epithelial IL5RA promotes epithelial-mesenchymal transition in pulmonary fibrosis via Jak2/STAT3 cascade. Gut-brain axis interplay via STAT3 pathway: Implications of Helicobacter pylori derived secretome on inflammation and Alzheimer's disease. Targeting IL-6/STAT3 signaling abrogates EGFR-TKI resistance through inhibiting Beclin-1 dependent autophagy in HNSCC. The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness. STAT3-Mediated Ferroptosis is Involved in Sepsis-Associated Acute Respiratory Distress Syndrome. The constitutive activation of STAT3 gene and its mutations are at the crossroad between LGL leukemia and autoimmune disorders. DNA methylation-mediated repression of microRNA-410 promotes the growth of human glioma cells and triggers cell apoptosis through its interaction with STAT3. WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling. Entero-toxigenic Bacteroides fragilis contributes to intestinal barrier injury and colorectal cancer progression by mediating the BFT/STAT3/ZEB2 pathway. IL-37 Modulates Myocardial Calcium Handling via the p-STAT3/SERCA2a Axis in HF-Related Engineered Human Heart Tissue. Targeting C21orf58 is a Novel Treatment Strategy of Hepatocellular Carcinoma by Disrupting the Formation of JAK2/C21orf58/STAT3 Complex. IDH2/R140Q mutation confers cytokine-independent proliferation of TF-1 cells by activating constitutive STAT3/5 phosphorylation. Long noncoding RNA ABHD11-AS1 interacts with SART3 and regulates CD44 RNA alternative splicing to promote lung carcinogenesis. PTPN2 inhibits the proliferation of psoriatic keratinocytes by dephosphorylation of STAT3. Blocking EGR1/TGF-beta1 and CD44s/STAT3 Crosstalk Inhibits Peritoneal Metastasis of Gastric Cancer. Autocrine Regulation of Interleukin-6 via the Activation of STAT3 and Akt in Cardiac Myxoma Cells. Sciellin promotes the development and progression of thyroid cancer through the JAK2/STAT3 signaling pathway. Knockdown of liver cancer cell-secreted exosomal PSMA5 controls macrophage polarization to restrain cancer progression by blocking JAK2/STAT3 signaling. Splicing analysis of STAT3 tandem donor suggests non-canonical binding registers for U1 and U6 snRNAs. Tumor Necrosis Factor alpha-Induced Protein 8-Like 1 Binds to Protein Arginine Methyltransferase 1 to Suppress the Methylation of Signal Transducer and Activator of Transcription 3 and Cell Growth in Oral Squamous Cell Carcinoma. CD146[+]CAFs promote progression of endometrial cancer by inducing angiogenesis and vasculogenic mimicry via IL-10/JAK1/STAT3 pathway. MicroRNA-221-3p inhibits the inflammatory response of keratinocytes by regulating the DYRK1A/STAT3 signaling pathway to promote wound healing in diabetes. Inhibition of PRMT1 Suppresses the Growth of U87MG-Derived Glioblastoma Stem Cells by Blocking the STAT3 Signaling Pathway. Role of STAT3 in cancer cell epithelial-mesenchymal transition (Review). PDP1 promotes the progression of breast cancer through STAT3 pathway. STAT3 is a genetic modifier of TGF-beta induced EMT in KRAS mutant pancreatic cancer. Nuclear autoantigenic sperm protein facilitates glioblastoma progression and radioresistance by regulating the ANXA2/STAT3 axis. Decreased HMGCS1 inhibits proliferation and inflammatory response of keratinocytes and ameliorates imiquimod-induced psoriasis via the STAT3/IL-23 axis. STAT3 promotes cytoplasmic-nuclear translocation of RNA-binding protein HuR to inhibit IL-1beta-induced IL-8 production. ANXA9 facilitates S100A4 and promotes breast cancer progression through modulating STAT3 pathway. The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer. The binding of PKCepsilon and MEG2 to STAT3 regulates IL-6-mediated microglial hyperalgesia during inflammatory pain. KIAA0040 enhances glioma growth by controlling the JAK2/STAT3 signalling pathway. PLAU promotes cell proliferation and migration of head and neck cancer via STAT3 signaling pathway. EZH2 Promotes Multiple Myeloma Progression via STAT3 Pathway Activation. NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma. Serine/Threonine kinase 16 phosphorylates STAT3 and confers a JAK2-Inhibition resistance phenotype in triple-negative breast cancer. TSPAN6 reinforces the malignant progression of glioblastoma via interacting with CDK5RAP3 and regulating STAT3 signaling pathway. Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis. PRMT5-mediated methylation of STAT3 is required for lung cancer stem cell maintenance and tumour growth. PDIA3 driven STAT3/PD-1 signaling promotes M2 TAM polarization and aggravates colorectal cancer progression. Tripartite Motif-containing Protein 11 Silencing Inhibits Proliferation and Glycolysis and Promotes Apoptosis of Esophageal Squamous Cell Carcinoma Cells by Inactivating Signal Transduction and Activation of Transcription Factor 3/c-Myc Signaling. Fatty Acid Binding Protein-4 Silencing Inhibits Ferroptosis to Alleviate Lipopolysaccharide-induced Injury of Renal Tubular Epithelial Cells by Blocking Janus Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling. Daucosterol regulates JAK2-STAT3 signaling pathway to promote megakaryocyte differentiation. GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis. KLF4 Induces Colorectal Cancer by Promoting EMT via STAT3 Activation. UBE2T mediates SORBS3 ubiquitination to enhance IL-6/STAT3 signaling and promote lung adenocarcinoma progression. GBP1 promotes cutaneous squamous cell carcinoma proliferation and invasion through activation of STAT3 by SP1. STAT3-induced lncRNA GNAS-AS1 accelerates keloid formation by mediating the miR-196a-5p/CXCL12/STAT3 axis in a feedback loop. A human STAT3 gain-of-function variant drives local Th17 dysregulation and skin inflammation in mice. HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses. FGL1: a novel biomarker and target for non-small cell lung cancer, promoting tumor progression and metastasis through KDM4A/STAT3 transcription mechanism. De novo mutations promote inflammation in children with STAT3 gain-of-function syndrome by affecting IL-1beta expression. Histones Methyltransferase NSD3 Inhibits Lung Adenocarcinoma Glycolysis Through Interacting with PPP1CB to Decrease STAT3 Signaling Pathway. miR-135b-5p promotes gastric carcinogenesis by targeting CLIP4-mediated JAK2/STAT3 signal pathway. Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus. circNDUFA13 stimulates adipogenesis of bone marrow-derived mesenchymal stem cells via interaction with STAT3. STAT3 promotes NLRP3 inflammasome activation by mediating NLRP3 mitochondrial translocation. Downregulation of CIAPIN1 regulates the proliferation, migration and glycolysis of breast cancer cells via inhibition of STAT3 pathway. Zinc finger protein 263 promotes colorectal cancer cell progression by activating STAT3 and enhancing chemoradiotherapy resistance. SPRR1B+ keratinocytes prime oral mucosa for rapid wound healing via STAT3 activation.
		WikiPathways: ► ▼ Microtubule cytoskeleton regulation Regulatory circuits of the STAT3 signaling pathway Cancer immunotherapy by PD-1 blockade Non-small cell lung cancer PDGFR-beta pathway TCA cycle nutrient use and invasiveness of ovarian cancer Nuclear receptors meta-pathway ncRNAs involved in STAT3 signaling in hepatocellular carcinoma IL-6 signaling pathway Cell differentiation - index IL-9 signaling pathway PDGF pathway IL-10 anti-inflammatory signaling pathway MET in type 1 papillary renal cell carcinoma Adipogenesis Oncostatin M signaling pathway Hepatitis B infection Acute viral myocarditis Neural crest cell migration during development Serotonin receptor 2 and STAT3 signaling Notch signaling pathway (Netpath) IL-7 signaling pathway Androgen receptor signaling pathway Leptin-insulin signaling overlap IL-17 signaling pathway Clear cell renal cell carcinoma pathways Thyroid stimulating hormone (TSH) signaling pathway Chemokine signaling pathway Interferon type I signaling pathways mBDNF and proBDNF regulation of GABA neurotransmission Brain-derived neurotrophic factor (BDNF) signaling pathway Prolactin signaling pathway Extracellular vesicles in the crosstalk of cardiac cells Dopaminergic neurogenesis Interactions between immune cells and microRNAs in tumor microenvironment MicroRNAs in cardiomyocyte hypertrophy Thymic stromal lymphopoietin (TSLP) signaling pathway IL-5 signaling pathway Cell differentiation - expanded index Estrogen receptor pathway Transcription factors regulate miRNAs related to cardiac hypertrophy EGFR tyrosine kinase inhibitor resistance AGE/RAGE pathway Physiological and pathological hypertrophy of the heart Pancreatic adenocarcinoma pathway IL-2 signaling pathway Leptin signaling pathway EPO receptor signaling Development of pulmonary dendritic cells and macrophage subsets IL-4 signaling pathway Gastrin signaling pathway Prion disease pathway TGF-beta receptor signaling in skeletal dysplasias Mammary gland development pathway - Involution (Stage 4 of 4) Neuroinflammation and glutamatergic signaling IL-3 signaling pathway FOXP3 in COVID-19 Hepatocyte growth factor receptor signaling EGF/EGFR signaling pathway VEGFA-VEGFR2 signaling pathway Embryonic stem cell pluripotency pathways TGF-beta receptor signaling Kit receptor signaling pathway RAC1/PAK1/p38/MMP2 pathway Interleukin-11 signaling pathway Hepatitis C and hepatocellular carcinoma Cell migration and invasion through p75NTR Neural crest cell migration in cancer Reactome pathways: ► ▼ p-Y701-STAT1 and p-Y705-STAT3 dissociate from IL27:IL27 receptor STAT3 and STAT1 are phosphorylated by JAKs after IL27:IL27R interaction STAT1, STAT3 bind p-Y611-IL27RA from Interleukin-27:Interleukin-27 receptor complex JAK1,JAK2 bound to IL27RA:IL12RB2 receptor phosphorylate STAT1,STAT3 STAT1,STAT3 associate with IL27RA:IL12RB2 receptor p-STAT1, p-STAT3 dissociate from IL27RA:IL12RB2 receptor Association of CCT/TriC with other substrates during biosynthesis (unknown chaperone) Expression of STAT3-upregulated cytosolic proteins MYC gene expression is enhanced by E2F1, STAT3, and CEBPB and repressed by CEBPA Activated STAT3 positively regulates CEBPB transcription CEBPB and phospho-STAT3 bind the promoter of the MYC gene NPM-ALK-dependent CEBPB gene expression Expression of STAT3-upregulated nuclear proteins IL24:IL22RA1:p-JAK1:IL20RB binds STAT3 IL24:IL22RA1:p-JAK1:IL20RB:STAT3 phosphorylates STAT3 IL24:p-IL20RA:p-JAK1:IL20RB binds STAT1,STAT3 IL24:IL20RA:p-JAK1:IL20RB:STAT1,STAT3 phosphorylates STAT1 or STAT3 p-STAT3 dissociates from IL24:IL22RA1:p‑JAK1:IL20RB:p‑STAT3 p-STAT1,p-STAT3 dissociate from IL24:IL20RA:p-Y1022,Y1023-JAK1:IL20RB:p-STAT1, p-STAT3 FGFR1OP-FGFR1 phosphorylates STAT1 and STAT3 Expression of STAT3-upregulated extracellular proteins MECP2 binds the STAT5A gene ALK mutants bind STAT3 ALK mutants phosphorylate STAT3 CEBPB gene transcription is enhanced by phospho-CREB1 and phospho-STAT3 CSF3 dimer:2xp-4Y-CSF3R:LYN:p-Y-JAK1:p-JAK2:p-SYK:p-HCK:p-TYK2 binds STAT1,3,5 CSF3 dimer:2xp-4Y-CSF3R:LYN:p-Y-JAK1:p-JAK2:p-SYK:p-HCK:p-TYK2:p-Y-STAT1,3,5 dissociates yielding CSF3 dimer:2xp-4Y-CSF3R:LYN:p-Y-JAK1:p-JAK2:p-SYK:p-HCK:p-TYK2 and p-Y-STAT1,3,5 p-Y-JAK1,2 phosphorylates STAT1,3,5 in CSF3 dimer:2xp-4Y-CSF3R:LYN:p-Y-JAK1:p-Y-JAK2:p-TYK2 Expression of STAT3-upregulated plasma membrane proteins STAT3, STAT4 are phosphorylated by p-JAK2, p-TYK2 in IL23:IL23 receptor STAT3 binds to p-Y-IL23R in IL23:IL23 receptor STAT4 binds p-Y-IL23R in IL23:IL23 receptor p-Y693-STAT4, p-Y705-STAT3 dissociate from IL23:IL23 receptor IFNL1:p-Y343,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2:STAT1 phosphorylates STAT1, STAT2, STAT3, STAT4 and STAT5 p-STAT1, p-Y-STAT2, p-STAT3, p-STAT4, p-STAT5 dissociates from IFNL1:p-Y343,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2:p-STAT1,p-STAT2,p-STAT3,p-STAT4,p-STAT5 IFNL1:p-Y434,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2 binds STAT1, STAT2, STAT3, STAT4, STAT5 p-Y705,S727 STAT3 is acetylated STAT3 is phosphorylated downstream of active ALK Recruitment of STATs Phosphorylation of STATs Dimerization of STATs Disassociation and translocation of STATs to the nucleus Phosphorylation of STATs downstream of KIT mutants Recruitment of STATs by KIT mutants Dimerization of STATs downstream of KIT mutants Disassociation and translocation of STATs to the nucleus downstream of KIT mutants PRDM1 gene expression downstream of ALK signaling AcK685-p-Y705,S727 STAT3 and SIN3A bind the PDRM1 promoter IL2RG gene expression downstream of ALK signaling AcK685-p-Y705,S727 STAT3 and SIN3A bind the IL2RG promoter JAK2 phosphorylates STAT1/STAT3 JAK2 binds STAT1/3 STAT3 phosphorylation CD274 gene expression downstream of ALK signaling p‑Y705-STAT3 dissociates from IL19:IL20RA:p-JAK1:IL20RB IL19:IL20RA:p-JAK1:IL20RB:STAT3 phosphorylates STAT3 IL19:IL20RA:p‑JAK1:IL20RB binds STAT3 HDACs deacetylate p-STAT3 dimers STAT3 binds activated MET receptor MET phosphorylates STAT3 ALK- and STAT3-dependent HIF1A gene expression PTK6 phosphorylates STAT3 Expression of FASLG IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3 phosphorylates STAT3 and STAT5 p-Y-STAT3 and p-STAT5 dissociates from IL15:IL15RA:IL2RB:p-JAK1:IL2RG:p-JAK3:p-Y-STAT3:p-STAT5 IL15:IL15RA:p-Y-IL2RB:p-Y-JAK1:p-Y-IL2RG:p-Y-JAK3 binds STAT3 and STAT5 p-Y705-STAT3,p-Y641-STAT6 dissociate JAK1 phosphorylates STAT3,STAT6 STAT3,STAT6 bind p-Y-IL4R p-Y701-STAT1, p-Y705-STAT3, p-Y649-STAT5 dissociates from IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:p-Y705-STAT3 IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3 binds STAT1, STAT3, STAT5A or STAT5B IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:STAT3 phosphorylates STAT1, STAT3 or STAT5 IL21 receptor STAT phosphorylation IL21 receptor STAT binding STAT1,STAT3,STAT6 bind IL13:IL13R type II STAT1,STAT3,STAT6 phosphorylation p-Y-STATs dissociate Tyrosine phosphorylated IL6ST binds STAT1,STAT3 Tyrosine phosphorylation of STAT1, STAT3 by IL6 receptor Phosphorylated STATs are released Serine phosphorylation of STATs STAT3 is phosphorylated by TSLP:IL7R:CRLF2:STAT3 complex STAT3 binds TSLP:IL7R:CRLF2 p-STAT3 dissociates from TSLP:IL7R:CRLF2:p-STAT3 complex STAT3 is phosphorylated by p-Y-JAK1,P-Y-TYK2 IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2 binds STAT3 p-Y705-STAT3 dissociates from IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3 IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:PTPN11:IL10RB:p-TYK2 binds STAT3 IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:STAT3 phosphorylates STAT3 IL26:IL10RB:p-TYK2:IL20RA:p-JAK1 binds STAT1, STAT3 p-STAT1 and p-STAT3 dissociates from IL26:IL10RB:p-TYK2:IL20RA:p-JAK1 p-Y705-STAT3 dissociates from IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:p-Y705-STAT3 IL26:IL10RB:p-TYK2:IL20RA:p-JAK1:STAT1,STAT3 phosphorylates STAT1,STAT3 IL20:IL20RA:JAK1:IL20RB:p‑JAK2,p‑JAK3 binds STAT3 IL20:IL20RA:JAK1:IL20RB:p-JAK3,p-JAK2:STAT3 phosphorylates STAT3 p-STAT3 dissociates from IL20:IL20RA:JAK1:IL20RB:p-Y1007,Y1008-JAK2,p-JAK3 Phosphorylated STAT3 Dissociates from Leptin Receptor JAK2 Phosphoryates STAT3 in Response to Leptin Phosphorylated LEPR Binds STAT3 Expression of NDN,TP53 STAT3 activation STAT binds to the active receptor STAT binds to p-11Y PDGFRA extracellular domain dimers STAT binds to the mutant PDGFRA receptor POU5F1 (OCT4), STAT3 bind the SALL4 promoter Expression of STAT3 Expression of SALL4 STAP2 recruits STAT3 to PTK6 PTK6 phosphorylates STAT3 Expression of PTGS2 Expression of BCL2, BCL2L1 Phosphorylated STAT1, STAT3 form dimers STAT1 and STAT3 dimers translocate to the nucleus p-Y-STATs dimerize p-Y-STATs translocate to nucleus p-Y701-STAT1:p-Y705-STAT3 translocates to the nucleus p-STAT1 binds p-STAT3 p-Y701-STAT1 binds p-Y705-STAT3 p-Y701-STAT1:p-Y705-STAT3 translocates from the cytosol to the nucleus p-Y-STAT1,3,5 dimerize p-Y-STAT1,3,5 dimer translocates from the cytosol to the nucleoplasm p-Y-STAT1,3,5 dimer enhances expression of SOCS3 p-Y-STAT1,3,5 dimer binds SOCS1 gene p-Y-STAT1,3,5 dimer binds SOCS3 gene p-Y-STAT1,3,5 dimer enhances expression of SOCS1 Phosphorylated STAT3 Forms Dimers Phosphorylated STAT3 Dimer Translocates to the Nucleus p-Y705-STAT3 dimer translocates from cytosol to nucleoplasm p-Y705-STAT3 dimerizes p-Y705-STAT3, p-Y641-STAT6 dimerise p-Y705-STAT3 dimer, p-Y641-STAT6 dimer translocate to nucleus Expression of HSP90B1 STAT3 binds SOCS3 promoter STAT3 stimulates SOCS3 expression p-Y705-STAT3:p-Y693-STAT4 translocates to the nucleus p-Y705-STAT3 binds p-Y693-STAT4 p-Y-STAT3 binds p-STAT5 p-Y-STAT3:p-STAT5 translocates to the nucleus p-STAT3 dimer translocates from cytosol to nucleoplasm p-STAT3 dimerizes Expression of SOCS3 Phospho-STAT3 binds the promoter of the CEBPB gene p-Y705,S727-STAT3 dimerizes p-Y705, p-S727 STAT3 dimer translocates to the nucleus p-Y705, S727 STAT3 dimer binds HIF1A gene p-Y705, S727 STAT3 dimer binds CD274 gene
		Transcript summary: Show transcripts retained_intron: 12 nonsense_mediated_decay: 5 protein_coding: 28 protein_coding_CDS_not_defined: 5 Transcript list: Hide transcripts ENST00000389272: 2615 bases (protein_coding) ENST00000678764: 5054 bases (retained_intron) ENST00000677479: 4731 bases (protein_coding) ENST00000677002: 3180 bases (protein_coding) ENST00000677763: 3027 bases (retained_intron) ENST00000677442: 4829 bases (protein_coding) ENST00000585360: 517 bases (retained_intron) ENST00000491272: 1327 bases (protein_coding_CDS_not_defined) ENST00000462286: 1248 bases (protein_coding_CDS_not_defined) ENST00000590776: 1483 bases (protein_coding_CDS_not_defined) ENST00000677346: 1486 bases (protein_coding_CDS_not_defined) ENST00000471989: 826 bases (retained_intron) ENST00000677820: 4879 bases (nonsense_mediated_decay) ENST00000677271: 4489 bases (nonsense_mediated_decay) ENST00000677270: 2680 bases (retained_intron) ENST00000678906: 4971 bases (protein_coding) ENST00000678674: 4703 bases (protein_coding) ENST00000677152: 3395 bases (protein_coding) ENST00000462269: 698 bases (retained_intron) ENST00000677603: 3314 bases (protein_coding) ENST00000679166: 4748 bases (protein_coding) ENST00000677421: 4911 bases (protein_coding) ENST00000678529: 2118 bases (retained_intron) ENST00000678108: 1927 bases (retained_intron) ENST00000678044: 4912 bases (protein_coding) ENST00000478276: 186 bases (retained_intron) ENST00000677723: 4834 bases (protein_coding) ENST00000588969: 2772 bases (protein_coding) ENST00000677500: 1277 bases (protein_coding_CDS_not_defined) ENST00000679014: 4890 bases (protein_coding) ENST00000678913: 4839 bases (protein_coding) ENST00000678535: 3288 bases (protein_coding) ENST00000679185: 4782 bases (protein_coding) ENST00000498330: 559 bases (retained_intron) ENST00000677030: 4812 bases (protein_coding) ENST00000585517: 3319 bases (protein_coding) ENST00000678445: 4944 bases (nonsense_mediated_decay) ENST00000678960: 4912 bases (protein_coding) ENST00000678827: 4800 bases (protein_coding) ENST00000678572: 4739 bases (protein_coding) ENST00000676636: 4822 bases (nonsense_mediated_decay) ENST00000679231: 4880 bases (retained_intron) ENST00000678792: 4842 bases (protein_coding) ENST00000264657: 4921 bases (protein_coding) ENST00000677308: 3374 bases (nonsense_mediated_decay) ENST00000678905: 4768 bases (protein_coding) ENST00000678043: 4837 bases (protein_coding) ENST00000404395: 2633 bases (protein_coding) ENST00000678659: 2866 bases (retained_intron) ENST00000678048: 4740 bases (protein_coding)
		UniProt: P40763 ► ▼ Signal transducer and activator of transcription 3 (Acute-phase response factor) FUNCTION: Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:15653507, PubMed:16285960, PubMed:17344214, PubMed:18242580, PubMed:18782771, PubMed:22306293, PubMed:23084476, PubMed:28262505, PubMed:32929201). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:15653507, PubMed:16285960, PubMed:17344214, PubMed:18782771, PubMed:28262505, PubMed:32929201). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): acetylation promotes its transcription activity and cell differentiation while deacetylation and oxidation of lysine residues by LOXL3 inhibits differentiation (PubMed:28065600, PubMed:28262505). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity). Following JAK/STAT signaling activation and as part of a complex with NFATC3 and NFATC4, binds to the alpha-beta E4 promoter region of CRYAB and activates transcription in cardiomyocytes (By similarity). . PDB: 5AX3 5U5S 6NJS 6NUQ 6QHD 6TLC Gene Ontology molecular function: transcription cis-regulatory region binding RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription activator activity, RNA polymerase II-specific DNA binding DNA-binding transcription factor activity nuclear receptor activity signaling receptor binding protein binding protein kinase binding protein phosphatase binding chromatin DNA binding signaling adaptor activity identical protein binding protein homodimerization activity protein dimerization activity RNA polymerase II-specific DNA-binding transcription factor binding primary miRNA binding DNA-binding transcription factor binding RNA sequestering activity localisation: chromatin nucleus nucleoplasm transcription regulator complex cytoplasm cytosol plasma membrane RNA polymerase II transcription regulator complex biological process: ► ▼ negative regulation of transcription by RNA polymerase II temperature homeostasis eye photoreceptor cell differentiation regulation of DNA-templated transcription regulation of transcription by RNA polymerase II protein import into nucleus defense response inflammatory response signal transduction transforming growth factor beta receptor signaling pathway receptor signaling pathway via JAK-STAT nervous system development cell population proliferation negative regulation of cell population proliferation negative regulation of autophagy positive regulation of gene expression negative regulation of gene expression phosphorylation cytokine-mediated signaling pathway sexual reproduction cell differentiation positive regulation of cell migration intracellular receptor signaling pathway response to estradiol positive regulation of interleukin-1 beta production positive regulation of interleukin-10 production positive regulation of interleukin-6 production positive regulation of interleukin-8 production positive regulation of tumor necrosis factor production cellular response to hormone stimulus leptin-mediated signaling pathway somatic stem cell population maintenance interleukin-15-mediated signaling pathway interleukin-2-mediated signaling pathway interleukin-9-mediated signaling pathway interleukin-11-mediated signaling pathway regulation of multicellular organism growth regulation of cell population proliferation glucose homeostasis eating behavior mRNA transcription by RNA polymerase II response to peptide hormone phosphatidylinositol 3-kinase/protein kinase B signal transduction cellular response to leptin stimulus response to leptin positive regulation of erythrocyte differentiation positive regulation of Notch signaling pathway positive regulation of angiogenesis negative regulation of glycolytic process positive regulation of DNA-templated transcription positive regulation of transcription by RNA polymerase II astrocyte differentiation negative regulation of inflammatory response positive regulation of NF-kappaB transcription factor activity regulation of cell cycle radial glial cell differentiation retinal rod cell differentiation regulation of feeding behavior growth hormone receptor signaling pathway growth hormone receptor signaling pathway via JAK-STAT interleukin-6-mediated signaling pathway T-helper 17 type immune response T-helper 17 cell lineage commitment energy homeostasis cellular response to interleukin-17 negative regulation of inflammatory response to wounding positive regulation of cytokine production involved in inflammatory response positive regulation of miRNA transcription positive regulation of metalloendopeptidase activity positive regulation of vascular endothelial cell proliferation negative regulation of primary miRNA processing negative regulation of stem cell differentiation negative regulation of neuron migration Domains PFAM: SH2 domain , STAT protein, all-alpha domain , STAT protein, DNA binding domain , STAT protein, protein interaction domain InterPro: SH2 domain , Transcription factor STAT , p53-like transcription factor, DNA-binding domain superfamily , STAT transcription factor, DNA-binding, N-terminal , STAT transcription factor, protein interaction , STAT transcription factor, all-alpha domain , STAT transcription factor, DNA-binding , STAT transcription factor, coiled coil , STAT3, SH2 domain , STAT transcription factor, N-terminal domain superfamily , SH2 domain superfamily

Data Updates

entity	last update (YYYY-MM-DD)
ClinVar	2022-09-13
ClinVar (likely) pathogenic variants	2024-12-27
Ensembl protein families	2023-08-17
Ensembl:Genbank (Biomart)	2024-12-02
Ensembl:Genbank (MANE)	2024-12-02
Entrez gene RIFS	2024-10-18
Entrez gene history	2024-10-18
Entrez gene positions	2024-10-18
Entrez gene synonyms	2024-10-18
Entrez genes	2024-10-18
Gene Ontology	2023-08-06
HPO	2023-10-12
HPO / OMIM	2023-10-12
HPO / Orphanet	2023-10-12
HPO / genes	2023-10-11
Interpro protein domains	2023-08-17
MGD/OMIM	2023-06-28
MGD/broad phenotypes	2023-07-05
NCBI Entrez gene/Ensembl (Enseml Biomart)	2024-12-02
NCBI Entrez gene/Ensembl (HGNC)	2024-12-02
NCBI Entrez gene/Ensembl (MANE)	2024-12-02
NCBI Entrez gene/Ensembl (NCBI gene2ensembl)	2024-12-02
OMIM	2023-08-02
Orphanet	2023-08-23
Orphanet:HPO frequencies	2023-08-23
Pfam	2023-08-17
STRING (v12)	2023-08-13
Swissprot/Uniprot IDs	2023-08-17
gnomAD gene constraints	2024-04-10