p28Gankyrin经由keap1-Nrf2通路正调控肝癌细胞抗氧化应激损伤的机制研究

项目名称： p28Gankyrin经由keap1-Nrf2通路正调控肝癌细胞抗氧化应激损伤的机制研究

项目编号： No.81472591

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 谈冶雄

作者单位： 中国人民解放军第二军医大学

项目金额： 80万元

中文摘要： 细胞内活性氧（ROS）的水平受精细调控，一方面失调控引起的氧化应激损伤与细胞的癌变密切相关，另一方面肿瘤细胞又能劫持该调控机制应对氧化应激对自身的损伤，提高对化疗药物的耐受性。表达、结构、稳定性等受氧化还原状态影响的Nrf2等转录因子对氧化应激起核心调控作用。我们新近的研究表明，肝癌重要的癌蛋白 p28GANK可通过提高细胞内的抗氧化酶系统，降低细胞内ROS水平，抑制癌细胞发生凋亡。我们还发现，p28GANK通过抑制降解机制，上调对抗氧化酶系统起关键调控作用的Nrf2的水平。所以，我们设想 p28GANK可能通过提高Nrf2参与调节肝癌细胞内氧化应激耐受，从而使细胞在高能量代谢状态和化疗药物压力下下仍然维持细胞活力。本项目拟明确p28GANK经由NRF2调控肝癌细胞氧化应激耐受的作用，阐明调控的作用。项目有助全面认识p28GANK的促癌机制，为研发新的克服肝癌耐药性的药物提供靶标。

中文关键词： 肝细胞癌；氧化应激；Nrf2；Gankyrin

英文摘要： The homeostasis of cell Reactive Oxygen Species (ROS) is delicately regulated mainly through transcription factors such as Nrf2. While per-oxidative damage always promote carcinogenesis and development of hepatocellular carcinoma(HCC), the cancer cell also hijacked this mechanism for its escape from damage induced by oxidative stress and enhanced resistance against chemotherapy. Recently, we found that p28Gank, a novel onco-protein in HCC, could up-regulate the anti-oxidant enzymes, thereby reducing ROS level and protecting the tumor cell from apoptosis. Furthermore, Nrf2, the key molecule for transcription of various anti-oxidant enzymes, is increased by p28Gank. In this project, we would like to confirm the role of Nrf2 in p28Gank induced anti-oxidant up-regulation and clarify its significance and mechanism.The implement of this project is prospected to deepen the knowledge on p28Gank-induced carcinogenesis and identify novel target for reverse of HCC chemotherapy resistance. Our research group has been focusing on P28Gank-centered signalling pathway for years, some achievments of which have been published in peer-viewed journals such Gastrotenterology,Hepatology and Cell Research.The platforms as well as technologies involved in this project are availabe in our lab or through co-operation with other lab.

英文关键词： hepatocellular carcinoma;oxidative stress;Nrf2;Gankyrin