BILE ACIDS AND GENE EXPRESSION IN COLON APOPTOSIS

胆汁酸和结肠凋亡中的基因表达

• 批准号: 6296137
• 负责人: JESSE D. MARTINEZ
• 金额: $ 13.05万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6296137
• 关键词: DNA footprinting; apoptosis; biological signal transduction; chemical carcinogenesis; chemoprevention; cholanate compound; colon neoplasms; gel mobility shift assay; gene expression; genetic regulatory element; human tissue; laboratory rat; neoplasm /cancer genetics; protein kinase C; site directed mutagenesis; tissue /cell culture; ursodeoxycholate

For almost 50 years, fecal bile acids have been implicated in playing an important role in colon carcinogenesis. This durable hypothesis has been supported by a variety of lines of evidence drawn from comparisons of the structure of bile acids to various carcinogens, epidemiological studies showing a relationship between increased fecal bile acids and colon cancer prevalence, and more recent studies demonstrating the genotoxic effects of bile acids, particularly for deoxycholic acid the predominant bile acid in stool. Despite such strong evidence linking fecal bile acids and colon cancer the mechanism of bile acid tumor promotion is not understood. Bile acids are known to induce apoptosis and since a critical step in the development of colon tumors is loss of the ability to undergo apoptosis, it has been suggested that bile acids provide a selective pressure that promotes the outgrowth of apoptosis resistant cells. Consequently, the capacity to induce apoptosis is an important activity of bile acids. Related to this, we recently showed that bile acids activate expression of GADD153, a growth arrest and DNA damage gene, that is implicated in regulating cell growth and apoptosis. The focus of this proposal is on determining the relationship between bile acid induced apoptosis, activation of (GADD153 gene expression, and bile acid tumor promotion. The hypotheses to be tested in the proposed studies are that bile acids induce apoptosis by activating the expression of GADD153 and that GADD153 becomes dysregulated in tumor cells. The specific aims are: 1) identify the cis-acting element in the GADD153 promoter that is responsive to bile acids, 2) identify the signaling pathway by which bile acids cause transactivation of the GADD153 gene and induction of apoptosis in colon cancer cells, 3) determine whether ursodeoxycholic acid, which suppresses tumor development, modifies the expression of GADD153 or the occurrence of apoptosis in preneoplastic aberrant crypt foci and in neoplasms from azoxymethane treated rats and in colonic mucosal samples and neoplasms taken from patients and from subjects treated with ursodeoxycholic acid.

近 50 年来，粪便胆汁酸一直与发挥作用有关。 在结肠癌发生中起重要作用。这个持久的假设已经被 得到了从比较中得出的各种证据的支持 胆汁酸结构与各种致癌物的流行病学研究 显示粪便胆汁酸增加与结肠癌之间的关系 患病率，并且最近的研究证明了遗传毒性作用 胆汁酸，特别是脱氧胆酸，它是体内主要的胆汁酸 凳子。尽管有如此强有力的证据表明粪便胆汁酸与结肠有关 胆汁酸促进肿瘤的机制尚不清楚。胆汁 已知酸会诱导细胞凋亡，并且因为这是细胞凋亡的关键步骤 结肠肿瘤的发展是细胞凋亡能力的丧失， 有人认为胆汁酸提供了一种选择压力 促进抗凋亡细胞的生长。因此， 诱导细胞凋亡的能力是胆汁酸的一项重要活性。 与此相关的是，我们最近表明胆汁酸激活 GADD153，一种生长停滞和 DNA 损伤基因，与 调节细胞生长和凋亡。该提案的重点是 确定胆汁酸诱导细胞凋亡之间的关系， 激活 (GADD153 基因表达，促进胆汁酸肿瘤。 在拟议的研究中要测试的假设是胆汁酸 通过激活 GADD153 的表达来诱导细胞凋亡，并且 GADD153 肿瘤细胞失调。具体目标是：1）确定 GADD153 启动子中对胆汁有反应的顺式作用元件 酸，2) 确定胆汁酸引起的信号通路 GADD153 基因的反式激活和结肠细胞凋亡的诱导 癌细胞，3) 确定熊去氧胆酸是否抑制 肿瘤的发展，改变 GADD153 的表达或发生 肿瘤前异常隐窝病灶和肿瘤中的细胞凋亡 氧化偶氮甲烷处理的大鼠以及结肠粘膜样本和肿瘤 取自接受熊去氧胆酸治疗的患者和受试者。