二甲双胍对肝细胞癌的抑制作用及机制研究

项目名称： 二甲双胍对肝细胞癌的抑制作用及机制研究

项目编号： No.31201026

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 郑龙轶

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： 原发性肝癌是我国最常见的恶性肿瘤之一，糖尿病已经成为继肝炎之后引发肝癌的另一重要危险因素。二甲双胍属于双胍类口服降糖药，临床上被广泛应用于2型糖尿病的药物治疗。随着研究的不断深入，发现二甲双胍同时具有抑制肿瘤生长的作用。对肝癌患者的回顾性研究亦发现二甲双胍治疗能降低糖尿病患者肝细胞癌的发生率，对肝细胞癌的进展也有保护作用。在本实验室的前期工作中，通过体外对肝细胞癌细胞系的研究，我们同样发现二甲双胍对肝癌细胞系具有抑制增殖和促进凋亡的作用。本课题拟在前期研究的基础上，运用分子生物学和细胞生物学的实验方法，进一步研究二甲双胍对肝癌细胞系增殖、凋亡、对化疗药物敏感性、体内成瘤能力的影响，以及对大鼠DEN诱导肝癌模型中肝癌发生、发展的影响，并从AMPK、NF-κB、IL-6/STAT3等信号途径阐述二甲双胍发挥抗肿瘤作用的具体分子机制，为研究二甲双胍在肝细胞癌的辅助性治疗中的作用提供理论依据。

中文关键词： 肝细胞癌；AMPK；二甲双胍；IL6/STAT3；NF-κB

英文摘要： Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality worldwide. Type 2 diabetes mellitus is an independent risk factor for HCC. Metformin is a biguanide commonly used to treat type 2 diabetes mellitus. The anti-diabetic drug metformin reduces human cancer incidence and improves the survival of cancer patients, including those with hepatocellular carcinoma. However, its biological and molecular activity against HCC is still not well understood. This project is therefore undertaken to evaluate the potential anti-tumoral activity of metformin in HCC and the mechanisms responsible for metformin action. Our previous research showed that metformin treatment significantly inhibited proliferation of diverse HCC cancer cell lines (SMMC7721, HCC-LM3) in a time- and dose-dependent manner. It also induced apoptosis and caused cell cycle arrest accompanied by decreased cyclin D1.Importantly, oral treatment with metformin led to a significant reduction of tumor growth in mice bearing xenografts of HCC-LM3. In this project, by using using molecular and cellular biology methods (proliferation assay, colony formation assay, cell cycle analysis, western blot, real-time quantitative PCR, etc.), we will clarify the inhibitory effect of metformin in both human HCC cel

英文关键词： Hepatocellular carcinoma；AMPK；metformin；IL6/STAT3；NF-κB