Mechnism Of SOCS3 Mediated IL-6/STAT3 Inflammatory Pathway In Colorectal Cancer And Its Significance

Background: Colorectal cancer is a common malignat tumor, in which the inflammatory microenviroment plays an important role. STAT3 signaling pathway is regarded as the “bridge” between inflammation and cancer, and involved in the development of colorectal cancer. SOCS3 is a key negative feedback regulator of JAK/STAT signaling pathway. Recent years, more and more studies focused on the abnormal expression of SOCS3 in various tumors. However, studies about SOCS3 gene in colorectal cancer are ralely reported. Our study aimed to explore the regulatory mechanism of SOCS3 expression in colorectal cancer and its role in colorectal cancer development, which may offer new theoretical basis and potential therapeutic targets for the treatment of colorectal cancer.Methods: 1. Differential expression of IL-6/pSTAT3/SOCS3 signaling among colorectal cancer tissues, matched pericancerous tissues were detected by Western blot and immunohistochemistry tests. Besides, we observed SOCS3 expression in colorectal cancer tissue microarray and correlated with the clinical pathological characteristics and prognosis of colorectal caners. 2. 1) Effects on expression of SOCS3 in colorectal cancer cell lines after treatment with IL-6 and stattic were studied by WB and QPCR. 2). Methylation status of SOCS3 gene promoter region was detected by MSP after treatment with IL-6 and stattic. We also evaluated SOCS3 protein expression induced by IL-6 in the presence of 5-Aza-cdR. 3).We evaluated the roles of IL-6/STAT3 sigaling pathway on transcription of SOCS3 gene promoter by dual luciferase reporter gene experiments. 3. We observed the effects of SOCS3 gene on biological behavior of colorectal cancer cells through apoptosis, proliferation, migration, invasion and tumor formation in nude mice.Results: 1.We observed that SOCS3 expression was down-regulated in colorectal cancer tissues, while IL-6, pSTAT3 were up-regulated by immunohistochemistry and WB. Low expression of SOCS3 in colorectal cancer tissue microarray by immunohistochemical analysis correlate with lymph node metastasis and advanced clinical stage. Patients with high expression of SOCS3 in colorectal cancers often indicated a relatively good prognosis. 2. 1) Inflammatory cytokines IL-6 can promote the expression of STAT3 signaling pathways and also increase the global DNA methylation level of colorectal cancer. STAT3 activation promoted hypermethylation of SOCS3 gene promoters. 5-Aza-cdR treatment can reverse IL-6/STAT3 signaling pathway mediated down-regulation of SOCS3 in colorectal cancer cells. 3).We observed that phosphorylated STAT3 supressed SOCS3’s transcription activity by dual luciferase report gene tests. 3. Overexpression of SOCS3 inhibited proliferation, migration, invasion and tumorigenetic ability of pancreatic cancer cells and cell apoptosis, inhibition of activation of STAT3 and the expression of MMP2 and MMP9.Conclusions: We demonstrated that activated IL-6/STAT3 signaling could induce SOCS3 methylation, which led to imbalance and sustained activation of STAT3 signaling pathway. The reduced expression of SOCS3 promoted the growth and metastasis of colorectal cancer. Thus, targeting IL-6/STAT3 signaling pathway may become an important treatment strategy of colorectal cancer.