Abstract OPS01-02: Inflammation and cancer: Interweaving microRNA, innate immune, and p53 pathways

Abstract

Abstract Infection and chronic inflammation contribute to the etiology and pathogenesis of about one in four of all cancer cases. Mediators of the inflammatory response, e.g., cytokines, free radicals, prostaglandins, non-coding RNAs, and growth factors, can induce genetic and epigenetic changes including point mutations in tumor suppressor genes, DNA methylation and posttranslation modifications, causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer (1-6). IL-6 and IL-8 cooperate with microRNA in the induction of cellular senescence in benign tumors (7-9) and as autocrine growth factors in carcinoma (10-14). Cellular senescence is also a tumor suppressor mechanism of p53 (15,16). We are studying the molecular mechanisms of cellular senescence in normal and malignant human cells and the role of the telomeric multiprotein complex, shelterin, that includes TRF2 and POT1. Our ongoing studies have revealed that p53 and its endogenous isoforms regulate both specific microRNAs and TRF2 expression as mechanisms of replicative senescence. In addition, POT1 isoforms are functionally diverse in both maintaining telomeric integrity and preventing p53-dependent senescence induced by telomeric shortening (17,18). A switch in the expression patterns of p53 isoforms 133Np53 and p53 beta can cause cellular senescence in vitro and is also associated with the transition of benign to malignant human colon tumors in vivo (19). Expression of microRNAs and inflammatory genes are biomarkers of cancer risk, diagnosis, prognosis, and therapeutic outcome. We are especially interested in the interaction of the innate immune pathway with environmental tobacco smoking in lung cancer risk (20) and the interaction of inflammatory cytokines, p53 isoforms, and microRNAs as prognostic classifiers of early stage lung and colon cancer and their functional role in the development of micrometastases [reviewed in (3)] (21-25).