Abstract 1225: Regulation of ARE-mediated mRNA decay during colorectal tumorigenesis

Abstract Colon cancer is mediated through various genetic alterations that promote the initiation and progression of tumorigenesis. As a consequence of these defects, overexpression of many oncogenic factors promoting enhanced cell growth and inflammation are observed. In the normal intestinal epithelium, oncogenic factor gene expression is controlled through AU-rich mRNA elements (AREs) that target mRNA for rapid decay. However, ARE-mRNA turnover is compromised during colon tumorigenesis resulting in a 3- to 4-fold enrichment in ARE-containing genes. To better understand how loss of ARE-mRNA decay contributes to colon tumorigenesis, the role of the mRNA decay factor tristetraprolin (TTP) in normal and tumor cells was examined. The RNA-binding protein TTP binds ARE motifs and promotes rapid mRNA decay by sequestering the mRNA to cytoplasmic sites known as processing bodies (P-bodies). Here, we demonstrate that treatment of non-transformed intestinal epithelial cells with TGF-B inhibited ARE-mRNA expression. This effect of TGF-B occurred through a Smad-dependent induction of TTP expression and this led to a 2-fold increase in cytoplasmic P-body assembly. These findings indicate that induction of post-transcriptional regulation is a novel growth-inhibitory feature of TGF-B in normal cells. Colon cancer progression is frequently characterized by the presence of activating mutations in the RAS proto-oncogene, and, in this context, the tumor-promoting effects of TGF-B signaling are observed. Using an intestinal epithelial cell model stably transfected with an inducible oncogenic Ras cDNA, we determined the impact of oncogenic cellular transformation on TTP expression. In cells expressing oncogenic Ras, the expression of TTP was decreased and these cells were rendered refractory to TGF-B-mediated TTP induction. The functional significance of this loss of TTP expression in transformed cells is observed with a 2-fold decrease in P-body formation. Consistent with this, colon cancer cells and tumor tissue show decreased TTP expression compared to normal tissue and a respective loss of P-body formation. Taken together, these results demonstrate that loss of the mRNA decay factor TTP occurs during colon tumorigenesis, thereby compromising ARE-mRNA decay and resulting in stabilization of various cancer-associated mRNAs. Through its ability to modulate expression of a majority of oncogenic factors, these findings define a role for TTP in tumor-suppressor capacity in the context of colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1225.