Post-Transcriptional Regulation in Colorectal Cancer

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DESCRIPTION (provided by applicant): Colorectal cancer is a leading cause of cancer mortality among adults. Commonly observed in colon cancer cells and tumors is overexpression of many growth- and inflammation-associated immediate-early response genes. A critical point in controlling the expression of these factors in normal intestinal epithelium occurs through post-transcriptional mechanisms that regulate mRNA decay. The two primary RNA-binding proteins associated with post-transcriptional regulation are the mRNA stability factor Hu antigen R (HuR) and the mRNA decay factor tristetraprolin (TTP). Both of these factors bind AU-rich mRNA elements (ARE) present in a majority of cancer-associated immediate-early response gene transcripts and target the mRNA for stabilization or rapid decay. However, a characteristic feature observed in colon cancer cells and tumors is overexpression of the stability factor HuR and loss of expression of the decay factor TTP. These combined defects allow for stabilization and overexpression of cancer-associated growth factors. Based on these observations we hypothesize that loss of post-transcriptional regulation promotes intestinal epithelial cell tumorigenesis by selectively stabilizing AU-rich element containing-mRNA transcripts. The following specific aims are proposed to test this hypothesis. Specific Aim 1: Determine whether altered expression of the mRNA stability factor HuR and the mRNA decay factor TTP can promote intestinal cell transformation and tumorigenesis. Under Aim 1 we will determine whether HuR overexpression and TTP loss play a causal role in promoting epithelial cell transformation and tumorigenesis through a mechanism of defective rapid mRNA decay and cancer-associated gene overexpression. Specific Aim 2: Determine the ability of low-molecular- weight inhibitors of HuR and viral-mediated delivery of TTP to impact colon cancer cell growth and gene expression. The emphasis of this aim is to investigate the therapeutic potential of targeting HuR-mediated mRNA stabilization. Specific Aim 3: Determine if HuR overexpression and TTP loss in the murine gastrointestinal tract promotes cancer-associated gene expression and tumorigenesis in vivo. In this Specific Aim we will determine the in vivo significance of HuR overexpression and TTP loss in promoting intestinal tumorigenesis. Specific Aim 4: Determine the molecular events in colon cancer cells and tumors that promote HuR overexpression and silencing of TTP expression. Under this aim, we will determine the mechanisms promoting HuR expression and TTP gene silencing in colon cancer. This study will enhance our understanding of colorectal cancer biology and lead to the identification of novel molecular targets, which will improve current treatment and prevention strategies.