Abstract 5744: Chronic inflammation activates IL6 signaling to upregulate DNMT1 and DNMT3b to promote colon tumorigenesis

Abstract

Abstract A strong correlation has been well documented between chronic inflammation and tumorigenesis. Colitis Associated Cancer (CAC) stands as a solid example for the inflammation-mediated tumorigenesis and is considered as the most serious complication of inflammatory bowel diseases. Pro-inflammatory cytokines are believed to regulate the neoplastic transformation of colonic epithelial cells. However, the underlying mechanism of inflammation-driven tumorigenesis is still a matter of debate. As a key player in the tumor inflammatory microenvironment, the pro-inflammatory cytokine IL6 is one of the most extensively studied cytokine in tumor biology research. IL6 is a pleiotropic cytokine secreted by different cell types including macrophages, fibroblast, epithelial cells and myeloid cells. IL6 and its downstream oncogenic transcription factor STAT3 have been shown to act as a tumor promoter through stimulating the proliferation and growth of malignant cells, inhibiting cell death and maintaining the inflammatory tumor-promoting milieu. Moreover IL6 protein and mRNA levels were found to be elevated in serum and tumor specimen from human and mice with different types of cancers including colon cancer; suggesting that IL6 may play a pro-tumorigenic function during the chronic inflammation-mediated tumorigenesis. However, the molecular mechanisms underlying IL6 tumor-promoting functions in CAC is still elusive. In this study, we aimed at determining the expression profiles and underlying mechanism of function of IL6 in the colon. Our data indicate that IL6 is significantly elevated in the colon in DSS-induced colitis mouse model and in AOM-DSS induced-CAC. Interestingly, myeloid derived suppressor cells (MDSCs) were shown to be the major source of IL6 in the lamina propria in vivo and in vitro .Given the role of IL6/STAT3/DNMTs axis in tumor promotion, we further hypothesized that IL6 may directly contribute to the inflammation-mediated colon tumorigenesis. To test our hypothesis, we generated IL6-overexpressing colon cancer cell lines and observed that IL6 overexpression is associated with STAT3 phosphorylation and resultant DNMT1 and DNMT3b upregulation in colon cancer cells. Similarly, treatment of colon cancer cells with exogenous IL6 induces STAT3 phosphorylation and up-regulation of DNMT1 and DNMT3b. Moreover, IL6-overexpression alters cell proliferation and survival. Collectively, our data highlighted a new crucial role of IL6 in the inflammation-mediated tumorigenesis through epigenetic alteration of colonic epithelial cells; suggesting that prolonged autocrine and paracrine IL6 signaling creates an inflammatory microenvironment favors tumor initiation and growth. Citation Format: Mohammed L. Ibrahim, John D. Klement, Daneila Payne, Chunwan Lu, Priscilla S. Redd, Kebin Liu. Chronic inflammation activates IL6 signaling to upregulate DNMT1 and DNMT3b to promote colon tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5744.