去泛素化酶USP14调控细胞周期相关蛋白在原发性肝细胞癌增殖中的机制和功能研究

项目名称： 去泛素化酶USP14调控细胞周期相关蛋白在原发性肝细胞癌增殖中的机制和功能研究

项目编号： No.81201555

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： 黄罡

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： 我们在对大量原发性肝癌样本的表达谱分析中发现去泛素化酶家族中USP14特异性的在肝癌组织中高表达，并在mRNA和蛋白水平进行确认。随访发现USP14高表达患者其肿瘤分期及预后均较差。进一步在肝癌细胞系SMMC7721中发现USP14表达较高，敲减USP14后，细胞周期明显改变，增殖明显抑制，凋亡比例增多，初步发现USP14可能具有促进肝癌生长的作用。再结合相关领域文献，我们认为USP14可能通过影响细胞周期相关蛋白稳定性对肝癌细胞的增殖调控起到关键作用。我们将首先通过大样本的免疫组化来进一步验证USP14的表达与肝癌分期及预后的相关性。进而再通过多种肝癌细胞系的体外、体内实验，研究该基因对肝癌细胞生物学特性的影响。并希望能在机制方面明确该基因与细胞周期调控相关蛋白之间的调控关系。最终为原发性肝癌发生发展的恶性异常调控机制相关研究打开新的切入点，同时为原发性肝癌的综合治疗提供新的治疗靶点。

中文关键词： 肝细胞癌；去泛素化酶；细胞增殖；预后；

英文摘要： Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide. Hepatic resection is a well-accepted therapy for HCC, but many patients are unable to surgery because of late HCC diagnosis, and alternative treatments do not substantially improve the patients' prognosis when HCC is unresectable. The investigation of molecular mechanisms leading to HCC development and progression is mandatory to identify new targets for its early diagnosis and treatment. Dysfunction of the ubiquitin proteasome system (UPS) has been implicated in numerous diseases, the preeminent of which is cancer. In our previous study, we found that the ubiquitin-specific peptidase 14（USP14） expression in the HCC tissues was significantly higher than those in the adjacent non-cancerous liver and normal liver tissue. Moreover, increased USP14 expression was associated with certain clinical pathological variables, such as advancing tumor stage. The Kaplan-Meier analysis demonstrated that HCC patients with USP14 overexpression had a significantly poor prognosis after surgery, compared with the patients with decreased levels of USP14. Knockdown of USP14 in SMMC7721 cells with siRNA and shRNA-lentivirus can suppress cell proliferation and induce cell apoptosis. These findings strongly suggest that USP14 activation might play an oncogenic

英文关键词： Hepatocellular carcinoma；ubiquitin-specific peptidase；proliferation；prognosis；