利用新型小鼠模型研究脂肪合成途径在Akt/Ras诱导的肝癌发生中的作用

项目名称： 利用新型小鼠模型研究脂肪合成途径在Akt/Ras诱导的肝癌发生中的作用

项目编号： No.81201553

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 李蕾

作者单位： 华中科技大学

项目金额： 23万元

中文摘要： 临床及实验研究表明肝癌发生和肝脏脂肪代谢失衡有关。我们发现Akt诱导的脂肪合成可以促使非肿瘤肝组织向肿瘤组织转化，在体外阻断脂肪合成可以抑制肝癌细胞依赖于AKT/mTOR信号途径的快速生长。这些证据提示脂肪合成异常可能会促进肝癌发生，但目前还缺乏体内的直接证据证明。 为了探寻脂肪合成在体内促进肝癌发生的直接证据，本研究将应用脂肪酸合成酶FASN条件敲除小鼠模型（FASN flox/flox），结合高压注射转染小鼠肝癌模型(Akt/Ras诱导的肝癌模型)，来研究脂肪合成在肿瘤发生中的重要作用。我们试图确认脂肪生成是导致肝癌的潜在因素，并希望观察到FASN的缺失/关闭导致的脂肪合成阻断不但可以抑制Akt/Ras诱导的肝癌发生，而且能够在肿瘤发生后诱导肿瘤萎缩。总之，我们希望通过小鼠模型来探索脂肪合成通路在体内对肝癌发生的促进作用，从而加深我们对肝癌发生机理的认识，并为肝癌靶向治疗提供新靶点。

中文关键词： 肝细胞癌；脂肪酸合成酶；AKT；脂肪合成；

英文摘要： Hepatocellular carcinoma (HCC), commonly known as liver cancer, is one of the leading causes of cancer related death world-wide. Yet, molecular mechanisms underlying hepatic carcinogenesis are still poorly understood. Accumulating evidence has demonstrated that metabolic imbalance is one of the hallmarks of cancer. Besides the well-known Warburg effect, increased de novo fatty acid synthesis is another important alteration of tumor cell physiology. However, how the abnormal lipid metabolic pathway regulates signaling cascades and how it contributes to tumor development remain unknown. In our recent publication, we showed that in human liver samples, de novo lipogenesis is progressively induced from non-tumor liver toward HCC. Mechanistic studies demonstrated that AKT/mTOR signaling promotes lipogenesis both in vivo and in vitro, and inhibition of lipogenic pathway genes reduces proliferation and survival of human HCC cell lines, as well as AKT-dependent accelerated cell growth in vitro. Here, in this proposal, we are trying to uncovere a novel function of fatty acid synthase (FASN), the rate limiting enzyme in de novo fatty acid synthesis. We hope by studying the funcion of FASN in hepatic carcinogenesis induced by Akt/Ras, to illlustrate the role of lipogenesis in hepatic carcinogenesis. In a word, the over

英文关键词： HCC；FASN；AKT；Lipogenesis；