JAK/STAT/SOCS-signaling pathway and colon and rectal cancer.
ABSTRACT: The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth. We evaluated the association between genetic variation in JAK1 (10 SNPs), JAK2 (9 SNPs), TYK2 (5 SNPs), suppressors of cytokine signaling (SOCS)1 (2 SNPs), SOCS2 (2 SNPs), STAT1 (16 SNPs), STAT2 (2 SNPs), STAT3 (6 SNPs), STAT4 (21 SNPs), STAT5A (2 SNPs), STAT5B (3 SNPs), STAT6 (4 SNPs) with risk of colorectal cancer. We used data from population-based case-control studies (colon cancer n?=?1555 cases, 1,956 controls; rectal cancer n?=?754 cases, 959 controls). JAK2, SOCS2, STAT1, STAT3, STAT5A, STAT5B, and STAT6 were associated with colon cancer; STAT3, STAT4, STAT6, and TYK2 were associated with rectal cancer. Given the biological role of the JAK/STAT-signaling pathway and cytokines, we evaluated interaction with IFNG, TNF, and IL6; numerous statistically significant associations after adjustment for multiple comparisons were observed. The following statistically significant interactions were observed: TYK2 with aspirin/NSAID use; STAT1, STAT4, and TYK2 with estrogen status; and JAK2, STAT2, STAT4, STAT5A, STAT5B, and STAT6 with smoking status and colon cancer risk; JAK2, STAT6, and TYK2 with aspirin/NSAID use; JAK1 with estrogen status; STAT2 with cigarette smoking and rectal cancer. JAK2, SOCS1, STAT3, STAT5, and TYK2 were associated with colon cancer survival (hazard rate ratio (HRR) of 3.3 95% CI 2.01,5.42 for high mutational load). JAK2, SOCS1, STAT1, STAT4, and TYK2 were associated with rectal cancer survival (HRR 2.80 95% CI 1.63,4.80). These data support the importance of the JAK/STAT-signaling pathway in colorectal cancer and suggest targets for intervention.
Project description:Introduction Searching for new therapeutic possibilities constitutes a challenge for modern medicine and an answer to better understanding of molecular mechanisms of pro-inflammatory diseases. The JAK-STAT pathway plays an important role in the inflammatory processes, which is supported by the fact that its inhibitors are used to treat, for instance, psoriasis and rheumatoid arthritis. Aim To determine whether the epigenetic mechanisms – methylation of gene promotion regions and miRNAs may serve as a new therapeutic strategy for JAK-STAT pathway inhibition. Material and methods Basing on MethPrimer (plus CpG Island Prediction) program and microrna.org database of the said mechanism in the regulation of the JAK-STAT signalling pathway, the gene expression was performed, indicating or excluding the possibility of their use as new potential therapeutic strategies. Results A different number of CpG islands (CGI) for each gene (JAK1-4 CGI; JAK2-2 CGI; JAK3-5 CGI, TYK2-6 CGI; STAT1-2 CGI; STAT2-1 CGI; STAT3-3 CGI; STAT5A-4 CGI; STAT5B-3 CGI) might be a new therapeutic goal. What is more, our results show that genes associated with JAK-STAT signalling pathways can be regulated by miRNAs (JAK1-42 miRNAs; JAK2-47 miRNAs; JAK3-15 miRNAs, TYK2-4 miRNAs; STAT1-17 miRNAs; STAT2-30 miRNAs, STAT3-36 miRNAs, STAT4-15 miRNAs; STAT5A-10 miRNAs; STAT5B-23 miRNAs). Conclusions The epigenetic mechanisms of the regulation of the JAK-STAT signalling pathway gene expression constitute a promising new therapeutic strategy for treatment of those diseases, during which disorders are observed in gene expression models of the analysed signalling pathway.
Project description:Impaired function of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway genes leads to immunodeficiency and various hematopoietic disorders. We evaluated the association between genetic polymorphisms (SNPs) in 12 JAK/STAT pathway genes (JAK3, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, SCOS1, SCOS2, SCOS3, and SCOS4) and NHL risk in a population-based case-control study of Connecticut women. We identified three SNPs in STAT3 (rs12949918 and rs6503695) and STAT4 (rs932169) associated with NHL risk after adjustment for multiple comparison. Our results suggest that genetic variation in JAK/STAT pathway genes may play a role in lymphomagenesis and warrants further investigation.
Project description:Hepatocellular carcinoma (HCC) is one the most common malignancies and has poor prognosis in patients. The aim of the present study is to explore the clinical significance of the main genes involved in the Janus kinase (JAK)?signal transducer and activator of transcription (STAT) pathway in HCC. GSE14520, a training cohort containing 212 hepatitis B virus?infected HCC patients from the Gene Expression Omnibus database, and data from The Cancer Genome Atlas as a validation cohort containing 370 HCC patients, were used to analyze the diagnostic and prognostic significance for HCC. Joint?effect analyses were performed to determine diagnostic and prognostic significance. Nomograms and risk score models were constructed to predict HCC prognosis using the two cohorts. Additionally, molecular mechanism analysis was performed for the two cohorts. Prognosis?associated genes in the two cohorts were further validated for differential expression using reverse transcription?quantitative polymerase chain reaction of 21 pairs of hepatitis B virus?infected HCC samples. JAK2, TYK2, STAT3, STAT4 and STAT5B had diagnostic significance in the two cohorts (all area under curves >0.5; P?0.05). In addition, JAK2, STAT5A, STAT6 exhibited prognostic significance in both cohorts (all adjusted P?0.05). Furthermore, joint?effect analysis had advantages over using one gene alone. Molecular mechanism analyses confirmed that STAT6 was enriched in pathways and terms associated with the cell cycle, cell division and lipid metabolism. Nomograms and risk score models had advantages for HCC prognosis prediction. When validated in 21 pairs of HCC and non?tumor tissue, STAT6 was differentially expressed, whereas JAK2 was not differentially expressed. In conclusion, JAK2, STAT5A and STAT6 may be potential prognostic biomarkers for HCC. JAK2, TYK2, STAT3, STAT4 and STAT5B may be potential diagnostic biomarkers for HCC. STAT6 has a role in HCC that may be mediated via effects on the cell cycle, cell division and lipid metabolism.
Project description:The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth; genetic variation in this pathway could influence breast cancer risk. We examined 12 genes in the JAK/STAT/SOCS signaling pathway with breast cancer risk and mortality in an admixed population of Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,585 controls) women. Associations were assessed by Indigenous American (IA) ancestry. After adjustment for multiple comparisons, JAK1 (three of ten SNPs) and JAK2 (4 of 11 SNPs) interacted with body mass index (BMI) among pre-menopausal women, while STAT3 (four of five SNPs) interacted significantly with BMI among post-menopausal women to alter breast cancer risk. STAT6 rs3024979 and TYK2 rs280519 altered breast cancer-specific mortality among all women. Associations with breast cancer-specific mortality differed by IA ancestry; SOCS1 rs193779, STAT3 rs1026916, and STAT4 rs11685878 associations were limited to women with low IA ancestry, and associations with JAK1 rs2780890, rs2254002, and rs310245 and STAT1 rs11887698 were observed among women with high IA ancestry. JAK2 (5 of 11 SNPs), SOCS2 (one of three SNPs), and STAT4 (2 of 20 SNPs) interacted with cigarette smoking status to alter breast cancer-specific mortality. SOCS2 (one of three SNPs) and all STAT3, STAT5A, and STAT5B SNPs significantly interacted with use of aspirin/NSAIDs to alter breast cancer-specific mortality. Genetic variation in the JAK/STAT/SOCS pathway was associated with breast cancer-specific mortality. The proportion of SNPs within a gene that significantly interacted with lifestyle factors lends support for the observed associations.
Project description:Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor.
Project description:The goal of this study was to determine the role of the Janus tyrosine kinase (JAK)-signal transducers and activators of transcription (STAT) pathway in the late phase of ischemic preconditioning (PC). A total of 230 mice were used. At 5 min after ischemic PC (induced with six cycles of 4-min coronary occlusion/4-min reperfusion), immunoprecipitation with anti-phosphotyrosine (anti-pTyr) antibodies followed by immunoblotting with anti-JAK antibodies revealed increased tyrosine phosphorylation of JAK1 (+257 +/- 53%) and JAK2 (+238 +/- 35%), indicating rapid activation of these two kinases. Similar results were obtained by immunoblotting with anti-pTyr-JAK1 and anti-pTyr-JAK2 antibodies. Western analysis with anti-pTyr-STAT antibodies demonstrated a marked increase in nuclear pTyr-STAT1 (+301 +/- 61%) and pTyr-STAT3 (+253 +/- 60%) 30 min after ischemic PC, which was associated with redistribution of STAT1 and STAT3 from the cytosolic to the nuclear fraction and with an increase in STAT1 and STAT3 gamma-IFN activation site DNA-binding activity (+606 +/- 64%), indicating activation of STAT1 and STAT3. No nuclear translocation or tyrosine phosphorylation of STAT2, STAT4, STAT5A, STAT5B, or STAT6 was observed. Pretreatment with the JAK inhibitor AG-490 20 min before the six occlusion/reperfusion cycles blocked the enhanced tyrosine phosphorylation of JAK1 and JAK2 and the increased tyrosine phosphorylation, nuclear translocation, and enhanced DNA-binding activity of STAT1 and STAT3. The same dose of AG-490 abrogated the protection against myocardial infarction and the concomitant up-regulation of inducible NO synthase (iNOS) protein and activity observed 24 h after ischemic PC. Taken together, these results demonstrate that ischemic PC induces isoform-selective activation of JAK1, JAK2, STAT1, and STAT3, and that ablation of this response impedes the up-regulation of iNOS and the concurrent acquisition of ischemic tolerance. This study demonstrates that the JAK-STAT pathway plays an essential role in the development of late PC. The results reveal a signaling mechanism that underlies the transcriptional up-regulation of the cardiac iNOS gene and the adaptation of the heart to ischemic stress.
Project description:STAT1 mediates response to interferons and regulates immunity, cell proliferation, apoptosis, and sensitivity of Fanconi Anemia cells to apoptosis after interferon signaling; the roles of STAT1 in embryos, however, are not understood. To explore embryonic functions of STAT1, we investigated stat1b, an unstudied zebrafish co-ortholog of human STAT1. Zebrafish stat1a encodes all five domains of the human STAT1-alpha splice form but, like the human STAT1-beta splice variant, stat1b lacks a complete transactivation domain; thus, two unlinked zebrafish paralogs encode protein forms translated from two splice variants of a single human gene, as expected by sub-functionalization after genome duplication. Phylogenetic and conserved synteny studies showed that stat1b and stat1a arose as duplicates in the teleost genome duplication (TGD) and clarified the evolutionary origin of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 by tandem and genome duplication. RT-PCR revealed maternal expression of stat1a and stat1b. In situ hybridization detected stat1b but not stat1a expression in embryonic hematopoietic tissues. Morpholino knockdown of stat1b, but not stat1a, decreased expression of the myeloid and granulocyte markers spi and mpo and increased expression of the hematopoietic progenitor marker scl, the erythrocyte marker gata1, and hemoglobin. These results suggest that zebrafish Stat1b promotes myeloid development at the expense of erythroid development.
Project description:Background:Signal transducer and activator of transcription (STAT) proteins are well-known transcription factors that play an important role in the progression of cancer. However, the association between STAT family genes and hepatocellular carcinoma (HCC) remains unclear. This study investigates the expression level, the prognostic value and the potential mechanism of STAT family genes in HCC. Methods:Data from 365 HCC patients in The Cancer Genome Atlas (TCGA) database and 241 HCC patients in the Gene Expression Omnibus (GEO) database were used to investigate the diagnostic and prognostic values of STAT genes by survival analysis and nomogram. Gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of the STAT genes in the development of HCC. Results:Our results showed that STAT4/5B mRNA expression levels in HCC tissues were lower than those in normal tissues. Importantly, our results indicated that high expression of STAT5A, STAT5B and STAT6 was associated with better overall survival in HCC patients. Joint effects analysis of STAT5A, STAT5B and STAT6 suggested that the prognosis difference for any combination of genes was more significant than that for any individual gene. Then, we developed a risk score model could predict HCC prognosis and the nomogram visualized gene expression and clinical factors of probability for HCC prognosis. The ROC and calibration curves showed good performance in survival prediction in both the TCGA and the GEO databases. GSEA suggested that high expression of STAT5A, STAT5B and STAT6 were involved in immune-related biological processes, drug metabolism cytochrome P450, JAK-STAT signalling pathway, and PPAR signalling pathways. Conclusion:Our data suggest that STAT5A, STAT5B and STAT6 expression may be potential prognostic markers of HCC and, in combination, have a better predictive value for HCC prognosis.
Project description:The past 10 years have seen enormous advances in our understanding of how cytokine signals are mediated intracellularly. Of particular significance was the discovery of a family of seven Signal Transducer and Activators of Transcription (STAT) proteins. Each of these has now been studied in detail, and appropriate gene-disrupted mouse models are available for all except STAT2 (Leonard and O'Shea 1998). Fetal lethality is observed in Stat3-deficient mice, and various immunodeficiencies characterize mice with disrupted Stat1, Stat4, and Stat6 genes, which is consistent with impaired signaling from the specific cytokines that activate each of these proteins. The recent characterization of Stat5-deficient mice has led to several unanticipated findings that point to diverse biological functions for the two STAT5 forms, STAT5a and STAT5b. These include roles for one or both STAT5 forms in the immune system, hematopoiesis, sexually dimorphic growth, mammary development, hair growth, deposition of adipose tissue, and pregnancy. Here we review the hormone- and cytokine-activated signaling pathways in which STAT5 participates and the extensive evidence, from laboratory animals, that these factors are required for sex-specific aspects of development, including control of body size. Finally, we consider human growth disorders that may involve defects in STAT5-dependent signal transduction.
Project description:Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds.