Although epidemiologic and experimental observations support the hypothesis that chronic inflammation and diet are risk factors for colorectal cancer, the mechanisms by which chronic inflammation and diet contribute to the development of cancer are poorly understood. Evidence for the link between inflammation and cancer comes from epidemiologic and clinical studies showing that use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the relative risk for developing colorectal cancer (CRC) by 40-50%. NSAIDs exert some of their anti-inflammatory and anti-tumor effects by targeting cyclooxygenase enzymes (COX-1 and COX-2). Metabolism of arachidonic acid, a major ingredient in animal fats, by cyclooxygenase enzymes provides one mechanism for the contribution of dietary fats and chronic inflammation to carcinogenesis. COX-2-derived prostaglandin E2 (PGE2) is a pro-inflammatory mediator that promotes tumor progression.
Considering the importance of PGE2 signaling in inflammation and colorectal carcinogenesis, the aim of our present study was to determine whether pro-inflammatory PGE2 is a mediator in connection of chronic inflammation to colorectal carcinogenesis. Here we revealed a novel function of proinflammatory PGE2 in regulating DNA methylation in colorectal cancer. Our in vitro and in vivo studies demonstrated that PGE2 treatment silenced certain tumor suppressors and DNA repair genes such as CDKN2B (p15), CNR1, MGMT, and MLH1 by enhancing CpG island methylation of their promoter via inducing DNMT1 and DNMT3B expression. We further found that a demethylating agent inhibited the effect of PGE2 on promoting tumor growth in a mouse model of colorectal cancer, indicating that PGE2 accelerates tumor growth via regulating DNA methylation. Furthermore, combined treatment of Apcmin/+ mice with inhibitors of COX-2 and DNA methylation has more effectively anti-tumor effects than either single agent alone. To further determine the clinical relevance of our in vitro and in vivo results, we examine the relationship between COX-2 expression, PGE2 levels, DNMT1/3b expression, CpG island methylation status and expression of these tumor suppressors and DNA repair genes in human colorectal carcinomas. The levels of COX-2 and PGE2 are positively correlated with DNMT1 and DNMT3B expression in these human colorectal cancer specimens. Importantly, the PGE2 levels as well as COX-2, DNMT1, and DNMT3B expression are also positively associated with the CpG island methylation in the promoters of these tumor suppressors and DNA repair genes. The expression levels of CNR1 (CB1), MGMT, and MLH1 are negatively correlated with their levels of CpG island methylation. Collectively, these findings uncover a previously unrecognized role for PGE2 promotion of tumor formation and progression.
Citation Format: Raymond N. DuBois, Dingzhi Wang. Inflammatory mediators and colorectal cancer progression. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PL02-03.