NDUFS1通过线粒体ROS/HIF-1α/FBLN5途径调控胃癌进展的研究

胃癌是一种发病率和死亡率高的消化道恶性肿瘤，亟需阐明其发生发展机制、寻找关键调控靶点，以期获得防治突破。本课题组利用iTRAQ技术研究发现，胃癌组织中NDUFS1表达下降、FBLN5表达升高。然而两者在胃癌中的作用、相互关系及其机制仍知之甚少。基于以往NDUFS1、FBLN5报道的提示，我们进一步预实验发现，NDUFS1缺失能促进胃癌生长、转移；并能促使胃癌细胞线粒体ROS升高，活化HIF-1α及上调靶基因FBLN5。因此我们推测：NDUFS1缺失可能通过激活线粒体ROS/HIF-1α/FBLN5途径参与胃癌的进展。为此，本项目拟以NDUFS1调控胃癌进展为研究主线，建立慢病毒介导的NDUFS1过表达、沉默胃癌细胞株，在细胞模型、动物模型及临床组织标本水平明晰NDUFS1/线粒体ROS/HIF-1α/FBLN5途径在胃癌中扮演的关键角色，探索和建立以NDUFS1为靶点治疗胃癌的新手段。

Gastric cancer is a common malignant tumor with high morbidity and mortality. It is urgent to clarify the mechanisms and find the key targets of its carcinogenesis and development, thus obtaining new breakthroughs in gastric cancer prevention and treatment. We previously found that the expression of NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1) was decreased, whereas the expression of fibulin-5 (FBLN5) was increased in gastric cancer clinical tissue specimens by isobaric tags for relative and absolute quantification (iTRAQ) analysis. However, the role and correlation of these two proteins in gastric cancer and its underlying mechanism is poorly unclear. Based upon the clue from previous reports on NDUFS1 and FBLN5, we performed preliminary studies and further demonstrated that NDUFS1 deficiency promoted the growth and metastasis in gastric cancer. NDUFS1 deficiency also increased mitochondrial reactive oxygen species (ROS), activated hypoxia-inducible factor-1α (HIF-1α) and upregulated HIF-1α downstream target FBLN5 in gastric cancer cells. Thus, we hypothesize that NDUFS1 deficiency would be involved in gastric cancer progression very possibly via activation of mitochondrial ROS/HIF-1α/FBLN5 pathway. For validation of the above hypothesis, the project will focus on regulatory effects of NDUFS1 in gastric cancer progression by establishing lentivirus-mediated NDUFS1-overexpressed or NDUFS1-knocked down gastric cancer cell line and then elucidating critical roles of NDUFS1/mitochondrial ROS/HIF-1α/FBLN5 pathway in gastric cancer at different levels including cell model, animal model and clinical samples, in order to explore and establish NDUFS1 as a novel target for gastric cancer treatment.