Abstract 4098: The HMGA1-COX-2 axis: A molecular pathway leading to tumor progression in human pancreatic adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma is a highly lethal cancer accounting for over 160,000 deaths worldwide each year. Despite the high prevalence of pancreatic cancer, the molecular events that lead to tumor progression are poorly understood. The high-mobility group A1 gene (HMGA1) is enriched in diverse, high-grade cancers and embryonic stem cells. This gene encodes the HMGA1a and HMGA1b chromatin remodeling proteins, which function in regulating gene expression. We previously showed that HMGA1 induces oncogenic transformation in cultured cells and causes aggressive cancers in transgenic mice. Moreover, we found that high HMGA1 protein levels correlate with poor differentiation status and decreased survival in a study of > 100 primary pancreatic ductal adenocarcinomas. These findings suggest that HMGA1 could drive a poorly differentiated, stem cell-like state and tumor progression in pancreatic ductal adenocarcinoma. In cultured, human pancreatic cells that overexpress K-RAS (HPNE-K-RAS cells), forced overexpression of HMGA1a leads to increased migration, invasion, and a transformed phenotype with anchorage-independent cell growth in soft agar. Because cyclooxygenase-2 (COX-2) is a downstream gene directly activated by HMGA1a in uterine cancers, we investigated the role of the HMGA1-COX-2 pathway in pancreatic adenocarcinoma. Our preliminary data suggest that HMGA1a and COX-2 mRNA levels are positively correlated in a pancreatic cancer cell lines. By chromatin immunoprecipitation, we found that HMGA1a binds to the COX-2 promoter in human pancreatic adenocarcinoma cells. Moreover, COX-2 inhibitors block tumorigenesis in human pancreatic cancer xenografts in nude mice. Taken together, our studies suggest that HMGA1a promotes tumor progression through up-regulation of COX-2 and this pathway could be targeted to treat or prevent human pancreatic adenocarcinoma. 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 4098.