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 在结肠癌发生中起重要作用。这个持久的假设一直是 通过各种证据的比较， 胆汁酸结构对各种致癌物的影响，流行病学研究 显示粪便胆汁酸增加和结肠癌之间的关系 流行率，以及最近的研究表明， 胆汁酸，特别是脱氧胆酸， 凳子尽管有如此强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 已知酸诱导细胞凋亡，并且由于细胞凋亡中的关键步骤， 结肠肿瘤的发展是经历细胞凋亡的能力的丧失， 已经提出胆汁酸提供选择性压力， 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可以激活 GADD 153是一种生长停滞和DNA损伤基因， 调节细胞生长和凋亡。该提案的重点是 确定胆汁酸诱导的细胞凋亡， GADD153基因表达的激活和胆汁酸肿瘤促进。 在拟议的研究中待检验的假设是，胆汁酸 通过激活GADD 153表达诱导细胞凋亡，GADD 153 在肿瘤细胞中变得失调。具体目标是：1）识别 GADD 153启动子中对胆汁应答的顺式作用元件 2）确定胆汁酸引起的信号通路 结肠中GADD 153基因的反式激活和细胞凋亡的诱导 癌细胞，3）确定是否熊去氧胆酸，抑制 肿瘤的发展，改变GADD 153的表达或肿瘤的发生。 肿瘤前异常隐窝病灶和肿瘤中的凋亡 氧化偶氮甲烷处理的大鼠和结肠粘膜样品和肿瘤中的 取自接受熊去氧胆酸治疗的患者和受试者。

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.