It is now well recognized that African Americans (AAs) exhibit disproportionately higher incidence and mortality rates for colorectal cancer (CRC) than European Americans/Caucasians (CAs). Also, black women are more likely to die from CRC than women in any other racial group and black men are even more likely to die from CRC than black women (Ginsburg CH, Clin Gastroentrol Hepatol 9: 859-61, 2011). Despite this grim outlook, little is known about the molecular and biochemical mechanisms for the racial disparity in CRC. Our ongoing mutation analysis of Apc and b-catenin genes revealed higher incidence of mutation of both Apc and b-catenin in colonic biopsies from AAs than CAs. Since cancer stem/stem-like cells (CSCs/CSLCs) are thought to be critically involved in the development and progression of many malignancies, including CRC, we also investigated whether the difference in CRC between AAs and CAs could partly be attributed to changes in CSCs/CSLCs. We observed that colon CSCs/CSLCs, specifically the proportion of CD44+CD166- phenotype, was markedly higher in colonic effluent, collected during colonoscopy, of AAs with adenomas than their CA counterparts. This increase was accompanied by a concomitant rise colonic mucosal microRNA-21 (miR-21), which has been shown to regulate CSCs/CSLCs. We hypothesize that the high incidence of CRC in AAs could be due to an increase in CSCs/CSLCs in the colon, in particular those with CD44+CD166- phenotype that exhibit increased mutation of tumor suppressor and/or proto-oncogenes, specifically Apc, k-ras and/or b- catenin. We will test this hypothesis by examining the mutational status of Apc, K-ras and/or b-catenin in CD44+CD166- CSCs/CSLCs, isolated from colonic biopsies and colonic effluent of AAs and CAs subjects with and without adenomas (Specific Aim 1). We also hypothesize that microRNA-21 (miR-21) plays a critical role in regulating colon CSCs/CSLCs. We will test this hypothesis (a) by examining the levels of miR-21 in CSCs/CSLCs, specifically in CD44+CD166- phenotype isolated from the normal appearing mucosa and colonic effluent of AAs and CAs with and without adenomas and also (b) by carrying out in vitro studies to examine the extent of changes in the proportion of CD44+CD166- phenotype following downregulation of miR- 21 (Specific Aim 2). Lastly, we will examine whether overall CSCs/CSLCs as well as CD44+CD166- phenotype isolated from normal appearing mucosa and colonic effluent of AAs with adenomatous polyps will possess greater tumorigenic properties in vitro and in vivo in SCID mice, compared to those from CAs (Specific Aim 3). The proposed study would not only give us a better understanding of the biological basis for the higher prevalence of CRC among AAs but would also lead to a new stratification strategy that would allow a better targeting of limited resources into screening of patients at the highest risk more intensely than those at lower risk.
Although African Americans (AAs) have higher incidence of colorectal cancer (CRC) and greater mortality from this disease than Caucasian Americans (CAs), little is known about the molecular mechanisms for the racial disparity in CRC. The proposed investigation is aimed at testing the hypothesis that the high incidence of CRC in AAs is due to an increase in self- renewing cancer stem or stem-like cells in the colon that exhibit increased mutations of genes, responsible for the development and progression of CRC and an increase in microRNA-21 that regulates cancer stem/stem-like cells. The proposed study would not only give us a better understanding of the biological basis for the higher prevalence of CRC among AAs, but could allow a better targeting of limited resources into screening of patients at the highest risk more intensely than those at lower risk.
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