Abstract 4243: HMGA1: A driver of the stem cell phenotype in intestinal cyrpt cells and colon cancer

Abstract

Abstract Although the HMGA1 gene is highly expressed in human embryonic stem cells and high-grade, poorly differentiated cancers, its function in these settings has not been clearly elucidated. The HMGA1 gene encodes the HMGA1a and HMGA1b protein isoforms, which are members of a family of non-histone, chromatin remodeling proteins. These proteins bind to the minor groove of AT-rich regions in the B-form of DNA, which leads to the recruitment of transcriptional factors that modulate gene expression. The HMGA1 gene is highly expressed during embryogenesis and in aggressive human cancers arising from different embryologic origins, including cancers of hematopoietic, lung, breast, prostate, and colon cells. Forced overexpression of HMGA1a or HMGA1b induces a transformed phenotype in cultured cells and inhibiting HMGA1 blocks transformation in human cancer cell lines. Because HMGA1 functions in transcriptional regulation, we hypothesize that it induces neoplastic transformation by dysregulating specific molecular pathways. To investigate the pathways disrupted by HMGA1, we are studying our HMGA1a transgenic mice as a model system. As previously reported, these mice develop aggressive T-cell leukemia with complete penetrance and females also develop uterine cancer. At necropsy, we also discovered polyps involving the small and large intestines. Histopathologically, the transgenic intestines are characterized by a thickened mucosal surface, hyperproliferative changes, and hamartomatous polyps. Immunohistochemical analysis reveals an increase in the population of intestinal cells expressing the colon stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr-5) in transgenic compared to wildtype mice. These data support our observation of an expansion in the crypt progenitor/intestinal stem cell populations. Our preliminary results also show that inhibiting HMGA1 expression in colon cancer cell lines interferes with anchorage-independent cell growth and tumorigenesis, indicating that HMGA1 is required for these transformation phenotypes in colon cancer. In addition, we found that HMGA1 is enriched in >70% of primary tumors with high-grade colon cancer. These findings suggest that HMGA1 is important in maintaining the stem cell niche in the intestine. Moreover, HMGA1 could promote neoplastic transformation and tumor progression in the intestine by driving a stem-like phenotype in colonic cells. 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 4243.