Cyclooxygenase-2 and TGF-beta Interactions in Intestinal Neoplasia

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DESCRIPTION: (Applicant's Description) We have developed evidence that TGF-betal induces the expression of COX-2 in intestinal epithelial cells, and that some of the responses to TGF-betal treatment appear to be dependent on COX-2. Long-term treatment of nontransformed intestinal epithelial cells results in loss of growth inhibition, downregulation of the type II TGF-beta receptor, and constitutive overexpression of COX-2, along with the acquisition of a fully transformed tumorigenic phenotype. There are several lines of experimental evidence to suggest that dysregulation of both COX-2 and TGF-beta signaling are important in tumorigenesis. We have observed remarkable concordance of expression of both TGF-beta1 and COX-2 in human colorectal tumors and in animal models of colon carcinogens and have developed evidence that there may be a regulatory relationship between COX-2 expression and the TGF-beta system. The central hypothesis for this project is that there is an important regulatory relationship between COX-2 and TGF-beta1, and that intestinal epithelial cell transformation results in a positive autocrine loop with overexpression of both COX-2 and TGF-beta1 resulting in enhanced tumor cell survival and tumor progression. The long-term goal of this project is to identify the mechanisms involved in the dysregulation of the COX-2 and TGF-beta systems during cell transformation and to identify novel molecular targets for chemoprevention and therapy of colorectal carcinoma. The central hypothesis will be tested experimentally with the following specific aims. Specific Aim 1. To determine whether TGF-beta regulates the expression of COX-2 during intestinal cell transformation. Specific Aim 2. To determine whether the transformed phenotype of the RIE-Tr cells and Ras-transformed RIE cells is dependent upon COX-2 expression (and prostaglandin synthesis). Specific Aim 3. To determine the mechanism of induction of COX-2 by TGF-beta1.