Colon Cancer Chemoprevention by Ursodeoxycholic Acid

熊去氧胆酸化学预防结肠癌

• 批准号: 6548254
• 负责人: SHARAD KHARE
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548254
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; carcinogenesis; cell line; chemoprevention; cholanate compound; colon neoplasms; gene expression; gene mutation; immunocytochemistry; mitogen activated protein kinase; neoplastic growth; northern blottings; prostaglandin endoperoxide synthase; tissue /cell culture; transfection; ursodeoxycholate; western blottings

DESCRIPTION (provided by applicant): My primary goal is to develop into an independent investigator in the field of colon-cancer chemoprevention. My long-term research objectives are to elucidate the mechanisms by which ursodeoxycholic acid exerts anticarcinogenic effects with respect to colon cancer. We have demonstrated that supplemental dietary cholic acid promoted the development of azoxymethane-induced rat colonic tumors. In contrast, dietary ursodeoxycholic acid (UDCA) inhibited tumorigenesis and suppressed cholic acid-induced tumor promotion. To examine the mechanisms by which UDCA causes anticarcinogenic effects, preliminary studies in the proposal demonstrated that UDCA inhibited Cox-2 gene expression at both the mRNA and protein levels and decreased Cox-2 immunostaining in stromal cells within the ACF. Furthermore, HCA-7 cells derived from a human colon cancer, demonstrated up-regulation of Cox-2 in response to deoxycholic acid (DCA). DCA is the major metabolite of the primary bile acid cholic acid, and is a potent tumor promoting bile acid. In contrast, UDCA inhibited DCA-induced Cox-2 up-regulation in HCA-7 cells, further supporting our hypothesis that the chemopreventive actions of UDCA involve, at least in part, the ability of UDCA to inhibit Cox-2 expression in colon cancer. HCA-7 cells, therefore, manifest a similar response to UDCA with respect to Cox-2 inhibition as observed in the AOM model. These cells will, therefore, serve as an ideal in vitro model to dissect the molecular events involved in Cox-2 dysregulation in colonic carcinogenesis. They will also allow us to identify potential mechanisms by which UDCA acts to inhibit Cox-2 expression, and thereby suppress tumorigenesis. In our Specific aims we propose to elucidate the signal transduction pathways and regulatory components by which DCA up-regulates Cox-2, while UDCA suppresses this induction. The current project fits well into my long-term research objectives to evaluate the molecular targets of this chemopreventive bile acid. Our findings in this proposal will also likely identify potential blomarkers that we will validate in a future study involving human ACF.

描述（由申请人提供）：我的主要目标是发展成为结肠癌化学预防领域的独立研究者。我的长期研究目标是阐明熊去氧胆酸对结肠癌发挥抗癌作用的机制。 我们已经证明，补充膳食胆酸促进氧化偶氮甲烷诱导的大鼠结肠肿瘤的发展。相反，膳食熊去氧胆酸（UDCA）抑制肿瘤发生和抑制胆酸诱导的肿瘤促进。为了检查UDCA产生抗癌作用的机制，该提案中的初步研究表明，UDCA在mRNA和蛋白水平上抑制考克斯-2基因表达，并降低ACF内基质细胞中的考克斯-2免疫染色。此外，来源于人结肠癌的HCA-7细胞证实了考克斯-2响应于脱氧胆酸（DCA）的上调。DCA是初级胆汁酸胆酸的主要代谢产物，并且是有效的促肿瘤胆汁酸。相比之下，UDCA抑制了HCA-7细胞中DCA诱导的考克斯-2上调，进一步支持了我们的假设，即UDCA的化学预防作用至少部分涉及UDCA抑制结肠癌中考克斯-2表达的能力。因此，HCA-7细胞对UDCA的考克斯-2抑制反应与AOM模型中观察到的相似。因此，这些细胞将作为一个理想的体外模型，以剖析参与考克斯-2失调在结肠癌发生的分子事件。它们还将使我们能够确定UDCA抑制考克斯-2表达的潜在机制，从而抑制肿瘤发生。在我们的具体目标中，我们建议阐明DCA上调考克斯-2而UDCA抑制这种诱导的信号转导途径和调控成分。 目前的项目非常适合我的长期研究目标，以评估这种化学预防胆汁酸的分子靶点。我们在该提案中的发现也可能识别出潜在的blomarkers，我们将在未来涉及人类ACF的研究中验证这些blomarkers。