REGULATION OF COX-2 EXPRESSION IN INTESTINAL NEOPLASIA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cyclooxygenases (COX) are key enzymes in prostaglandin synthesis and overexpression of inducible COX-2 has been shown to participate in pathogenesis of cancer and inflammatory syndromes. Recent data strongly associates the critical role of COX-2 in colorectal cancer development and implicate COX-2 expression as a rate-limiting step in intestinal epithelial cell carcinogenesis. Growing evidence indicates a central point of COX-2 gene regulation occurs at the post-transcriptional level through cis-acting elements present in the COX-2 mRNA. This AU-rich mRNA element (ARE) is present in the 3' untranslated region (3'UTR) of COX-2 and many cancer-associated mRNAs and targets them for rapid mRNA decay through interaction with cellular RNA-binding proteins. We have recently shown that the RNA binding protein HuR regulates COX-2 gene expression on a post-transcriptional level and demonstrated that COX-2 is aberrantly induced in tumors due in part to altered expression of this mRNA stability factor. We hypothesize that overexpression of HuR promotes intestinal epithelial cell tumorigenesis through stabilization of COX-2 and angiogenic factor mRNAs. This central hypothesis will be addressed with the following specific aims. Specific Aim 1: Determine if altered expression of the mRNA-stability factor HuR can promote intestinal cell transformation and tumorigenesis. Under Aim 1 we will determine the functional significance HuR has in promoting COX-2 expression in intestinal epithelial cells and determine the biological impact HuR-mediated mRNA stabilization has upon epithelial cell growth and tumorigenicity. Specific Aim 2: Determine if HuR overexpression in the murine gastrointestinal tract promotes COX-2 overexpression and tumorigenesis in vivo. Utilizing a transgenic mouse model, which recapitulates what is observed in human colorectal cell lines and tumors, we will examine the ability of HuR to promote COX-2 overexpression and intestinal tumorigenesis. Furthermore, we will determine if HuR-mediated mRNA stabilization can compensate for loss of a functional COX-2 allele. The long-term goal is to understand the mechanism by which loss of post-transcriptional regulation promotes COX-2 expression in colorectal cancer and define HuR as a new molecular target for therapeutic intervention.