Colorectal cancer (CRC) is a significant health concern in most industrialized countries. A significant effort has been made in the identification of drug targets for both the prevention and treatment of colorectal cancer over the past decade. Epidemiological, experimental, and clinical studies have demonstrated that there is a significant reduction in risk for colorectal cancer in persons who take nonsteroidal anti-inflammatory drugs (NSAIDs). A large body of genetic and biochemical evidence has demonstrated that the cyclooxygenase-2 (COX-2) enzyme is a promising NSAID target for prevention of colorectal cancer. In COX-2-dependent pathways, NSAIDs suppress colon carcinogenesis through the inhibition of prostaglandin formation. Studies by our group have demonstrated that 1) a synthetic PPARdelta agonist increases the number and size of polyps in Min mice; 2) COX-2 derived PGE2 induces PPARdelta transactivation; 3) PGE2 induces colon cancer cell migration/invasion through a EGFR-PI3k-Akt pathway; 4) NSAIDs downregulate a novel gene NRG-1 (NSAID regulated gene-1), which is highly expressed in human colorectal tumor tissue and is up-regulated by Ras. However, the precise mechanisms for the COX-2-dependent or -independent effects of NSAIDs on colorectal carcinogenesis are not clear. The experiments we propose here will explore these issues further and attempt to understand the mechanisms by which NSAIDs affect colorectal biology. Our experimental approaches will focus on the following three specific aims: 1) Determine the biologic function of PPARdelta in the intestinal polyp formation; 2) Characterize downstream pathways of COX-2 derived PGE2 in colorectal cancer biology; and 3) Characterize the biologic function of the NSAID-regulated gene-1 (NRG-1) in colorectal cancer formation.
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