Colorectal carcinoma, the second most common cancer in men and women in the U.S., is newly diagnosed in 150,000 persons each year. Chemoprevention through cyclooxygenase-2 (COX-2) specific NSAIDs is being proposed as a viable means of reducing the incidence of colorectal polyps, the precursors of colon cancer, and of progression from polyp to cancer. COX-2 expression is found in stromal intestinal myofibroblasts (IMFs) in premalignant colorectal adenomatous polyps and there is global activation (alpha smooth muscle actin expression) in these lamina propria stromal cells. The long term goal of this research is to explore the hypothesis that, in colorectal polyp IMFs, signaling via reactive oxygen species (ROS) and transforming growth factor beta (TGF() control both the activated phenotype and the expression of COX-2 at transcriptional and post-transcriptional levels. Using molecular techniques including Northern and Western analyses, RT-PCR, siRNA knockdown, confocal microscopy of single cell cytoplasm/nuclear molecule translocation and ROS generation, chromatin immunoprecipitation and analysis, and immunohistochemistry and confocal microscopy of human archival normal colon, polyp and cancer sections and primary isolated IMFs, we will address the following specific aims: 1) Identify the mechanisms responsible for ROS-mediated COX-2 transcriptional activation in isolated IMFs, 2) Establish which ROS activated signaling pathways mediate COX-2 mRNA stabilization in isolated IMFs, 3) Identify the mechanisms by which TGFbeta induces COX-2 expression in isolated IMFs and 4) Investigate and clarify how ROS and TGFbeta influence mesenchymal/epithelial interactions in a co-culture models of normal, polyp and carcinoma epithelial and stromal (IMF) cells. These studies will identify key pathways that mediate stromal activation early in the process of colorectal carcinogenesis and create new targets for the development of preventive strategies that will prevent progression to carcinoma.
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