乙醛脱氢酶2的激活剂美他多辛在肝癌发生发展过程中的功能及机制研究

As one of the most common digestive system cancers, Hepatocellular carcinoma (HCC) greatly threatens human health and becomes the third most frequent cause of cancer-related deaths all over the world. We previously compared gene and protein expression patterns between paired tumor and nontumor tissues from patients with HCC, ALDH2 were identified for further study. And we found that forced expression of ALDH2 in HCC cells inhibits their aggressive behavior in vitro and in mice by regulating AMPK signaling through modulating the ALDH2-acetaldehyde-redox-AMPK (AMP-activated protein kinase) axis. Additionally, it is the enhanced ALDH2 activity but not protein level that contributes largely for ALDH2-manipulated cell migration and invasion. Metadoxine is the first-line drug of alcoholic liver disease, by accelerating the elimination of acetaldehyde in plasma through strengthening the acetaldehyde dehydrogenase activity in cells. However, the role of metadoxine in HCC has not been studied exhaustively. Thus, we intended to further verify the effect of metadoxine on several biological characteristics (eg, proliferation, metastasis or apoptosis) of hepatoma cells in vitro and vivo. And then to explore the underlying mechanisms. The aim of our project is to verify the potential value of metadoxine in tumorgenesis and development of HCC. And our researches wound provide a novel therapeutic option for HCC patient, which may be helpful to improve the therapeutic effect and reduce the mortality of liver cancer.

肝癌严重威胁人民的健康和生命，我国的肝癌诊疗形势依然相当严峻。课题组前期通过对肝癌组织样本进行转录组和蛋白质组测序，经生物信息学分析，寻找到了在肝癌恶性进展过程中变化高频的酶，乙醛脱氢酶2（ALDH2），后续的研究发现，过表达ALDH2可以明显的抑制肝癌的侵袭和转移能力，并且这种功能可能是通过活化AMPK的相关机制实现的；同时，ALDH2也可以加速酒精代谢产物乙醛的清除而抑制肝癌的恶性进展。美他多辛作为酒精性肝病的一线用药，通过加强细胞内乙醛脱氢酶活性而加速血浆中乙醛的消除，而美他多辛对于肝癌的治疗作用未见明确报道。本项目拟从细胞水平上研究美他多辛对肝癌细胞生长、凋亡、转移和化疗敏感性的影响，而后结合动物模型研究美他多辛对肝癌的发生、发展和转移的抑制作用，并明确其相关的分子机制。本课题的完成将为肝癌的治疗提供新的思路，对提高肝癌的治疗效果和降低肝癌的死亡率具有积极意义和潜在的临床应用价值。

肝癌是一种高致死性肿瘤，其预后较差。我们前期研究发现乙醛脱氢酶2（ALDH2）在肝癌中发挥抑癌作用，但作为酒精性肝病一线用药的ALDH2激活剂美他多辛在肝癌中的作用尚不清楚。本研究为研究美他多辛对肝癌的作用，通过构建体内DEN联合CCL4诱导肝癌发生模型，我们发现美他多辛能抑制肝癌发生，功能实验发现美他多辛能抑制肝癌细胞增殖，促进肝癌细胞凋亡，抑制肝癌细胞转移，还可抑制肝癌干细胞扩增。本课题为肝癌的治疗提供新的思路，对提高肝癌的治疗效果具有积极意义和潜在的临床应用价值。

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