BILE ACIDS AND GENE EXPRESSION IN COLON APOPTOSIS

近50年来，粪便胆汁酸一直被认为是一种 在结肠癌的发生中起重要作用。这一持久的假设一直是 得到了各种证据的支持，这些证据来自于 胆汁酸对多种致癌物的结构、流行病学研究 显示粪便胆汁酸升高与结肠癌的关系 流行率，以及最近的研究表明， 胆汁酸，特别是脱氧胆酸是人体内的主要胆汁酸 凳子。尽管有如此有力的证据表明粪便胆汁酸和结肠 胆汁酸促进肿瘤的机制尚不清楚。胆汁 已知酸可诱导细胞凋亡，而且由于酸在细胞凋亡中的关键步骤 结肠肿瘤的发展是失去进行细胞凋亡的能力， 有人认为，胆汁酸提供了一种选择性压力， 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重要活性。 与此相关的是，我们最近发现胆汁酸能激活 GADD153，一个生长停滞和DNA损伤的基因，与 调节细胞生长和凋亡。这项提案的重点是 确定胆汁酸诱导细胞凋亡的关系， 激活(GADD153)基因表达，促进胆汁酸肿瘤的发生。 在拟议的研究中要检验的假设是胆汁酸 激活GADD153和GADD153的表达诱导细胞凋亡 在肿瘤细胞中变得失调。具体目标是：1)确定 GADD153启动子中对胆汁反应的顺式作用元件 酸，2)确定胆汁酸引起的信号通路 GADD153基因反式激活与诱导结肠细胞凋亡 癌细胞，3)确定熊去氧胆酸，它抑制 肿瘤的发展，改变GADD153的表达或发生 癌前异常隐窝病灶及非霍奇金淋巴瘤中细胞凋亡的研究 偶氮甲烷处理的大鼠以及结肠粘膜样本和肿瘤中 取自患者和接受熊去氧胆酸治疗的受试者。

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.