石胆酸在结直肠癌中通过诱导miR-21抑制PTEN表达的作用及机制研究

It was widely known that a western-style diet lead to high levels of bile acids and the development of colorectal cancer. Primary bile acids are amphipathic detergents that are synthesized in the liver and secreted with bile into the duodenum where they play an important role in digestion and absorption of dietary lipids. Most of bile acids are reabsorbed in the ileum and only small quantities reach the colon where they are converted by enteric bacteria to secondary bile acids such as lithocholic acid (LCA). LCA has been implicated as endogenous colorectal cancer promoter. PTEN, as an important tumor suppressor, has been reported to suppress colorectal cancer metastasis. Our study intends to investigate the effect of PTEN expression by LCA and the underlying mechanism. In previous study, we found that LCA inhibits PTEN expression in concentration- and time- dependent manners. And LCA increased miR-21 expression in colorectal cancer cells. In silico analysis indentified that miR-21 binding sites in the 3’-untranslated regions (3’-UTR) of PTEN-encoding gene. Therefore, we suppose LCA inhibits PTEN expression through the induction of miR-21 and thus induce colorectal cancer metastasis. In this study, we will apply the cell and molecular techniques to investigate the underlying mechanisms of the inhibition of PTEN and the detailed pathways of miR-21 induction by LCA. Based on the foregoing, the results of this study may provide a new insight into the obesity and a western-style diet-induced colorectal cancer and contribute to development of new strategies for colorectal cancer treatment.

高脂肪饮食方式增加结直肠癌的发病率已为人们所认识，但其机理尚不清楚。石胆酸是少量胆汁酸进入肠内由细菌代谢产生的物质，高脂肪饮食可增加人体肠组织中石胆酸的生成。抑癌基因PTEN可抑制结直肠癌的发生和发展已有公开报道。目前关于PTEN在石胆酸诱导的结直肠癌的发生和发展中的作用没有研究报道。前期研究中，申请人发现石胆酸可抑制结直肠癌细胞中PTEN的表达，并发现石胆酸上调miR-21的表达。miR-21可特异性的结合PTEN mRNA以抑制PTEN表达。因此我们推测石胆酸是通过诱导miR-21来抑制PTEN的表达，进而促进结直肠癌的发展。本课题拟应用细胞生物学，分子生物学，免疫学等技术在体内体外水平探讨石胆酸对PTEN的作用。确认在结直肠癌细胞中石胆酸是通过诱导miR-21的表达来抑制PTEN的表达，然后进一步明确其分子机制。这一研究将为高脂肪饮食方式促进的结直肠癌的发病机制提供新的解释。

高脂肪饮食方式增加肠癌的发病率已为人们所认识，但其机理尚不清楚。石胆酸是少量胆汁酸进入肠内由细菌代谢产生的物质，高脂肪饮食可增加人体肠组织中石胆酸的生成。抑癌基因PTEN可抑制肠癌的发生和发展已有公开报道。目前关于PTEN在石胆酸诱导的肠癌的发生和发展中的作用没有研究报道。前期研究中，申请人发现石胆酸可抑制肠癌细胞中PTEN的表达，并发现石胆酸上调miR-21的表达。miR-21可特异性的结合PTEN mRNA以抑制PTEN表达。因此我们推测石胆酸是通过诱导miR-21来抑制PTEN的表达，进而促进肠癌的发展。本课题拟应用细胞生物学，分子生物学，免疫学等技术在体内体外水平探讨石胆酸对PTEN的作用。确认在结直肠癌细胞中石胆酸是通过诱导miR-21的表达来抑制PTEN的表达，然后进一步明确其分子机制。这一研究将为高脂肪饮食方式促进的肠癌的发病机制提供新的解释。