BILE ACID INDUCED AP1 SIGNALING IN COLON CANCER

申请人的描述：本项目的总体目标是 描述胆汁酸改变结肠肿瘤病因的机制， 检测胆汁酸介导的信号转导变化的影响， 和基因表达对细胞命运的影响。脱氧胆酸（DCA）可以刺激 基因表达通过激活AP-1转录因子， ras/erk通路的调节，表明DCA作为肿瘤 启动子通过异常上调原癌基因活性和模拟 基因突变的影响。有趣的是，DCA还刺激了一个单独的 蛋白激酶C依赖性途径，也可能导致AP-1的上调 通过GSK-3在Wnt-1信号通路中起作用。有趣的是，熊去氧胆酸 熊去氧胆酸（UDCA）是一种具有化学预防特性的胆汁酸， AP-1活性。相反，UDCA刺激的信号传导与激活的 AP-1和/或PKC信号传导以诱导细胞凋亡。重要的是，我们已经确定 AP-1可能在Min（+）小鼠肿瘤中以及在胃粘膜的平坦粘膜中上调。 AOM在最终接触这种致癌物很长时间后对小鼠进行了治疗，这表明 AP-1在体内在促进肿瘤生长的条件下被异常激活 发展因此，我们假设胆汁酸调节结肠 通过改变信号转导导致激活 AP-1此外，我们推测UDCA可能具有化学预防作用， 通过选择性地诱导细胞凋亡的试剂，其中AP-1和/或PKC是 异常刺激我们将通过以下方式进行测试：1）确定DCA是否可以 改变Wnt-1信号传导的活性和/或使Wnt-1信号传导失调， APC基因生殖系突变对肿瘤促进/化学预防的影响 通过胆汁，3）表征UDCA介导的结肠源性 细胞系，4）确定UDCA是否可以诱导结肠癌细胞凋亡， 具有异常AP-1活性的上皮细胞，5）检查 补充UDCA的饮食对细胞内信号传导和基因表达有影响， 人体的结肠上皮。

APPLICANT'S DESCRIPTION: The overall objective of this project is to delineate the mechanism through which bile acids alter colon tumor etiology by examining the effect that bile acid-mediated changes in signal transduction and gene expression have on cell fate. Deoxycholic acid (DCA) can stimulate gene expression by activating the AP-1 transcription factor through up regulation of the ras/erk pathway, suggesting that DCA acts as a tumor promoter by aberrantly up regulating protooncogene activity and mimicking the effects of gene mutations. Interestingly, DCA also stimulates a separate protein kinase C-dependent pathway that may also cause up regulation of AP-1 through GSK-3 in the Wnt-1 signaling pathway. Interestingly, ursodeoxycholic acid (UDCA), a bile acid with chemopreventative properties, does not stimulate AP-1 activity. Instead, UDCA stimulated signaling cooperates with activated AP-1 and/or PKC signaling to induce apoptosis. Importantly, we have determined that AP-1 may be up-regulated in Min(+) mouse tumors and in the flat mucosa of AOM treated mice long after final exposure to this carcinogen, suggesting that AP-1 is aberrantly activated in vivo under conditions that foster tumor development. Consequently, we hypothesize that bile acids modulate colon cancer etiology by altering signal transduction that leads to activation of AP-1. Furthermore, we speculate that UDCA may function as a chemopreventive agent by selectively inducing apoptosis in cells where AP-1 and/or PKC is aberrantly stimulated. We will test this by: 1) determining whether DCA can modify the activity of and/or dysregulate Wnt-1 signaling, 2) examine the effect of germline mutations in the APC gene on tumor promotion/chemopreven-tion by bile, 3) characterize UDCA-mediated signaling activity in colon-derived cell lines, 4) determine whether UDCA can induce apoptosis in colonic epithelial cells with aberrant AP-1 activity, 5) Examine the effect that a diet supplemented with UDCA has on signal transduction and gene expression in the colonic epithelium of human subjects.