Abstract LB-263: Study of Hox gene expression in normal and malignant colonic tissues implicates Hox A4 and Hox D10 in the stem cell-origin of colon cancer

Abstract

Abstract Our goal was to identify transcriptional regulatory mechanisms that maintain stem cell (SC) population size in normal colonic epithelium because dysregulation, following acquisition of mutations, leads to tumor SC overpopulation, tumor initiation, and colon cancer. We used microarray analysis to identify a unique gene-expression pattern for a SC-enriched population (the bottom third of the normal human crypt, where colonic SC reside). Two-color microarray analysis (18,500 genes) was used to analyze gene expression in isolated crypt subsections (top [T], middle [M], and bottom [B] thirds). About 25% of known genes were expressed (showed hybridization to RNA from colonic epithelium). Several RNA species (n=287) were preferentially expressed in one of the three crypt subsections (T, M, or B). Six of the known genes up regulated in the bottom third of the crypt mapped to the P13 kinase pathway and two were Hox genes (Hox A4 and D10). Immunohistochemistry (IHC) was then used to analyze expression of Hox A4 and Hox D10 in human colonic tissues. IHC showed that both Hox A4 and D10 are expressed in cells residing at the bottom of the normal crypt and are co-expressed with aldehyde dehydrogenase 1 (ALDH1), a SC marker in these cells. Moreover, IHC showed that Hox A4 and D10 are overexpressed in tumors compared with normal colonic epithelium. These data represent the first gene-expression profiles for sub-regions of the human colonic crypt, especially the SC-rich crypt base, which we now know has a unique gene-expression signature. Co-expression of Hox A4 and D10 with ALDH1 in normal colonocytes suggests that these Hox genes have a role in regulation of the crypt SC population size. Overexpression of Hox A4 and D10 in colon cancer suggests that these Hox genes, when dysregulated, contribute to SC overpopulation and colon tumorigenesis. Identification of the Hox gene-based mechanisms that are involved in the regulation of normal crypt SC population size and in dysregulation of neoplastic SC populations could lead to identification of SC-based targets and ways to develop new, more effective treatments for advanced colon cancers. 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 LB-263.