Racial Disparity in Colorectal Cancer: Molecular Mechanisms

结直肠癌的种族差异：分子机制

• 批准号: 8492513
• 负责人: ADHIP P. N. MAJUMDAR
• 金额: $ 16.44万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492513
• 关键词: ALCAM gene; Adenomatous Polyps; African American; Age; American; Biochemical; Biological; Biopsy; CD44 gene; Cancer Etiology; Caucasians; Caucasoid Race; Cells; Cessation of life; Colon; Colon Carcinoma; Colonoscopy; Colorectal Cancer; Development; Diagnosis; Disease; Down-Regulation; Early Diagnosis; European; Exhibits; Gastroenterologist; Gene Mutation; Genes; High Prevalence; In Vitro; Incidence; Investigation; Lead; Malignant Neoplasms; MicroRNAs; Molecular; Mucous Membrane; Mutation; Mutation Analysis; Natural regeneration; Newly Diagnosed; Pathologist; Patients; Phenotype; Pilot Projects; Play; Property; Proto-Oncogenes; Race; Reporting; Resources; Risk; Role; SCID Mice; Scientist; Stratification; Testing; Tumor Suppressor Proteins; United States; Woman; adenoma; base; cancer cell; caucasian American; cohort; high risk; in vivo; men; mortality; multidisciplinary; outcome forecast; public health relevance; screening; self-renewal; stem; stemness; tumor; tumorigenic

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：目前已充分认识到，非裔美国人（AA）的结直肠癌（CRC）发病率和死亡率不成比例地高于欧洲裔美国人/高加索人（CA）。此外，黑人女性比任何其他种族群体的女性更可能死于CRC，黑人男性甚至比黑人女性更可能死于CRC（Ginsburg CH，Clin Gastroentrol Hepatol 9：859-61，2011）。尽管前景黯淡，但人们对CRC种族差异的分子和生化机制知之甚少。我们正在进行的Apc和b-连环蛋白基因突变分析显示，在AA的结肠活检组织中，Apc和b-连环蛋白的突变发生率高于CA。由于癌症干细胞/干细胞样细胞（CSC/CSLCs）被认为与许多恶性肿瘤（包括CRC）的发生和进展密切相关，因此我们还研究了AA和CA之间CRC的差异是否部分归因于CSC/CSLCs的变化。我们观察到，结肠CSC/CSLCs，特别是CD 44 + CD 166-表型的比例，在结肠镜检查期间收集的结肠流出物中，AA腺瘤比CA对应物明显更高。这种增加伴随着结肠粘膜microRNA-21（miR-21）的伴随增加，其已被证明可调节CSC/CSLC。我们假设AA中CRC的高发病率可能是由于结肠中CSC/CSLC的增加，特别是那些具有CD 44 + CD 166-表型的CSC/CSLC，这些表型表现出肿瘤抑制基因和/或原癌基因突变增加，特别是Apc、k-ras和/或B-连环蛋白。我们将通过检查CD 44 + CD 166-CSC/CSLC中Apc、K-ras和/或b-连环蛋白的突变状态来检验这一假设，这些CSC/CSLC分离自患有和不患有腺瘤的AA和CA受试者的结肠活检和结肠流出物（具体目标1）。我们还假设microRNA-21（miR-21）在调节结肠CSC/CSLC中起关键作用。我们将通过检查CSC/CSLC中miR-21的水平来检验这一假设（a），特别是从具有和不具有腺瘤的AA和CA的正常表现的粘膜和结肠流出物中分离的CD 44 + CD 166-表型，以及（B）通过进行体外研究以检查在miR- 21下调后CD 44 + CD 166-表型比例的变化程度（具体目标2）。最后，我们将研究从正常粘膜和伴有腺瘤性息肉的AA结肠流出物中分离的总体CSC/CSLC以及CD 44 + CD 166-表型是否在SCID小鼠中具有比CA更大的体外和体内致瘤特性（特异性目的3）。拟议的研究不仅可以让我们更好地了解AA中CRC患病率较高的生物学基础，还可以制定新的分层策略，以便更好地将有限的资源用于筛查最高风险患者，而不是低风险患者。