Abstract 3083: The RNA stability factor HuR promotes an angiogenic switch in colon cancer

Abstract

Abstract The initiation and progression of colorectal tumorigenesis is characterized by alterations in gene expression that allow for the overexpression of oncogenic and tumor-promoting factors. In normal cells, the mRNA transcripts of these cancer-associated genes are targeted for rapid decay through AU-rich elements (ARE) present in the mRNA 3’ untranslated region (3′UTR). However, growing evidence reveals that the loss of ARE-mediated mRNA decay is a characteristic feature contributing to pathogenic gene expression in colorectal cancer. Our prior work identified enhanced expression of the RNA-binding protein HuR to occur during colon tumorigenesis and HuR overexpression is correlated with poor clinical prognosis. In this capacity, HuR promotes overexpression of many cancer-associated factors by binding to their ARE and interfering with subsequent rapid mRNA decay. To determine the functional significance of HuR overexpression in vivo, a tissue-specific HuR-transgenic mouse (HuR-Tg) was created that overexpresses HuR in the epithelium of the small intestine and colon. HuR-Tg mice displayed normal growth and did not reveal any morphological changes in the gastrointestinal tract. To test if HuR overexpression can impact tumorigenesis downstream a tumor initiating event, crosses between HuR-Tg mice and the APCMin/+ mouse, a genetic model of gastrointestinal tumorigenesis, were performed. As early as 12 weeks of age, HuR-Tg/APCMin/+ lines display a 2- to 4-fold increase in tumor burden and size in both the colon and small intestine compared to APCMin/+control mice. Based on HuR's ability to bind various ARE-containing mRNAs associated with angiogenesis, vascular density was assayed in tissue derived from HuR-Tg/APCMin/+ mice. Micro-vessel density was 2-fold greater in the tumors and surrounding tissue in APCMin/+ mice overexpressing HuR. Angiogenic mRNA array analysis of tumors derived from HuR-Tg/APCMin/+ mice showed enhanced expression of multiple ARE-containing angiogenic genes including the HuR target genes vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Furthermore, dietary treatment of HuR-Tg/APCMin/+ mice with celecoxib attenuated HuR-dependent tumor formation and suppressed micro-vessel density and VEGF expression. These findings indicate that HuR functions during colon tumorigenesis downstream of a tumor-initiating event to stabilize ARE-containing mRNAs associated with tumor vascularization and identify this mRNA stability factor as a new molecular target for therapeutic intervention in controlling angiogenic gene expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3083. doi:10.1158/1538-7445.AM2011-3083