Mo1152 The Role of Cancer Stem Cells in the Increased Risk of Colorectal Cancer in African-Americans

Abstract

Background: Epidemiological studies have demonstrated that African-Americans (AAs) have a higher incidence of colorectal cancer (CRC) and greater mortality from this disease than Caucasians (CAs). The underlyingmechanisms for this increased risk are not well understood. We hypothesize that differences in the number and characteristics of a small subset of selfrenewing cancer stem/stem-like cells (CSCs) present within the colonic mucosa are responsible for the higher incidence of CRC in AAs. We also postulate that microRNAs (miRs), specifically miR-21, up-regulated in CRC and miR-145, which is down-regulated in CRC, play pivotal roles in regulating colon CSCs. Methods: Biopsies were obtained through a standardized protocol from normal-appearing colonic mucosa at the time of routine colonoscopy. Biopsies were subjected to collagenase/hyaluronidase digestion for isolation of CSCs (AJP:GI 302:G655-'63, 2012) and subsequently analyzed for CD44+CD166colon CSC phenotype, which we have previously found to be significantly higher in colonic mucosa of patients with tubular adenomas than those without adenomas (Dig. Dis. Sci. 57:2334'39, 2012). We also determined the expression of miR-21 and miR-145. In addition, the relative abundance of EGFR and β-catenin, that are known to be dysregulated in CRC, was examined by immunohistochemistry. Results: The current cohort includes 48 subjects, of which 63% were found to have adenomas. We have observed a 44.7% higher proportion of CD44+/CD166CSC phenotype in normal appearing colonic mucosa in AAs (27.12%; n=10) than CAs (18.74%; n=8). Likewise, the levels of miR-21 were 70% higher in the colonic mucosa of AAs with adenomas than CAs. In contrast, miR-145 levels were downregulated by 45% in AAs over the CA patients. The relative abundance of both EGFR and β-catenin in the colonic crypt of AAs was found to be 80% and 5-fold higher, respectively in AAs with adenomas than their CA counterparts. Conclusion: The increased risk for CRC in AAs might be explained by the increase CSCs in their colonic mucosa. miR-21 and miR-145, which also regulate EGFR, are thought to be involved in regulating CSCs in the colonic mucosa of AAs.