DIET AND MOLECULAR GENETICS OF COLONIC CANCER

饮食和结肠癌的分子遗传学

• 批准号: 2097637
• 负责人: LEONARD H AUGENLICHT
• 金额: $ 19.52万
• 依托单位: MONTEFIORE MEDICAL CENTER (BRONX, NY)
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-21 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2097637
• 关键词: adenoma; cancer risk; colorectal neoplasms; cytochrome oxidase; dietary fiber; family genetics; gene expression; gene mutation; genetic promoter element; human subject; intestinal mucosa; messenger RNA; mitochondrial DNA; molecular genetics; neoplasm /cancer genetics; nucleic acid sequence; nucleic acid structure; nutrition related neoplasm /cancer; nutrition related tag; posttranslational modifications; protein structure; short chain fatty acid; structural genes; transcription factor

Novel computer driven scanning and image processing methodology demonstrated that genetic inheritance of risk for colorectal cancer in familial polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) families is associated with highly pleiotropic affects on patterns of gene expression in the flat colonic mucosa. Among a panel of cloned sequences identified which characterize genetic risk, one is the mitochondrial (mt) encoded gene for the third subunit of mt cytochrome oxidase (COXIII). Expression was decreased in both progression of, and genetic risk for, colonic tumors in vivo, and metabolizable, unbranched, short-chain fatty acids (SCFAs) elevated these depressed levels of mtCOXIII expression, as well as mtCOXI, in colonic carcinoma cells in culture and also elevated mtCOX enzymatic activity, while leaving unaffected nuclear encoded subunits of COX. These changes may underlie the documented alterations in mitochondria structure and function in transformed colonic epithelial cells. Since SCFAs produced by fermentation of fiber by colonic microflora are the principle energy source for colonic epithelial cells, and since SCFAs also induce colonic epithelial cell differentiation both in vitro and in vivo, this suggests a mechanistic link between the molecular events in inherited risk and a dietary factor (fiber) which may modulate risk. To understand this relationship between diet and genetic risk, we will: l) determine SCFA affects on expression of genes on the mtDNA H and L strands in colonic carcinoma, adenoma and normal epithelial cells; 2) utilize a unique Utah kindred K353, in which gene carriers have variable penetrance of a mutation at the FAP locus on chromosome 5q21, to determine the relationship between the number of tumors which form and mt gene expression, and the impact of fiber intake in these patients on these two parameters; 3) determine mechanisms by which SCFAs elevate mt gene expression, including: the rate constants for mtRNA synthesis and degredation; structural alterations in the H and L strand bipartite promotors in tumors and tissue at risk; alterations in function and covalent modification of the major mt transcription factor mtTF1; and alterations in the mtTF1 nuclear encoded sequence in colonic tumors.

新颖的计算机驱动扫描和图像处理方法 证明了结直肠癌风险的遗传遗传 家族性息肉病（FAP）和遗传性非旋转性结肠癌（HNPCC） 家族与高度多效性有关基因模式的影响 在扁平结肠粘膜中的表达。 在克隆序列的面板中 确定哪种特征是遗传风险，一个是线粒体（MT） MT细胞色素氧化酶（Coxiii）的第三个亚基的编码基因。 表达在两者的进展和遗传风险中都降低 体内结肠肿瘤，可代谢，无分支，短链脂肪 酸（SCFA）将这些抑郁水平的mtcoxiii表达升高为 以及mtcoxi，在培养中结肠癌细胞中 MTCOX酶活性，同时留下未受影响的核编码 考克斯的亚基。这些变化可能是记录在 线粒体结构和功能转化的结肠上皮 细胞。 由于SCFA是通过结肠发酵产生的SCFA 菌群是结肠上皮细胞的主要能源， 而且由于SCFA还诱导结肠上皮细胞分化 在体外和体内，这表明了 遗传风险和饮食因素（纤维）中的分子事件可能 调节风险。 要了解饮食与遗传风险之间的这种关系，我们将：L） 确定SCFA影响mt​​DNA H和L链上基因的表达 在结肠癌，腺瘤和正常上皮细胞中； 2）使用a 独特的犹他州亲戚K353，其中基因载体具有可变的外渗 在5q21染色体上FAP基因座的突变，以确定 形成的肿瘤数量和MT基因的数量之间的关系 表达，以及纤维摄入对这两种患者的影响 参数; 3）确定SCFA升高MT基因的机制 表达，包括：mTRNA合成的速率常数和 退化； H和L链两分的结构变化 肿瘤和组织中的启动子；功能的改变和 主要MT转录因子MTTF1的共价修改；和 MTTF1核编码序列的变化。