USP14抑制β-catenin泛素化降解促进肺腺癌恶性增殖及其分子机制的研究

项目名称： USP14抑制β-catenin泛素化降解促进肺腺癌恶性增殖及其分子机制的研究

项目编号： No.81201850

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2

项目作者： 武宁

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： 研究肺癌的发生、发展机制，从中寻找早期诊断、预后判断的指标及新的治疗靶点始终是肺癌研究领域的热点。泛素/去泛素化系统的调节失衡与肿瘤的发生发展密切相关。基于前期在肺腺癌细胞株及手术标本中对去泛素化酶USP14的检测结果，以及发现USP14可能促进肺腺癌细胞株增殖的基础上，本课题拟采用基因干预技术，进一步从体内和体外两个层面明确内源性USP14对肺腺癌细胞恶性表型的影响；根据前期的USP14底物蛋白筛选结果，以β-catenin作为其主要靶蛋白，通过实验设计验证USP14通过对β-catenin的去泛素化调控而促进其在肺腺癌细胞内稳定表达，最终促进细胞增殖的分子机制。并检测300例肺腺癌临床样本，分析USP14的表达与肺腺癌患者病理学分级及预后等的相关性。希望通过本研究，对蛋白翻译后修饰在肿瘤发生发展中的作用提供新的认识，并为寻找肺腺癌诊断和预后判断指标及干预靶点奠定基础。

中文关键词： 肺腺癌；USP14；β-catenin；去泛素化；增殖

英文摘要： The ubiquitin proteasome system has been implicated in tumorigenesis. Lung adenocarcinoma is one of the most common cancer in the world in terms of the high incidence and poor outcome. USP14 gene, which codes for one kind of deubiquitinating enzyme, was found overexpressed in both lung adenocarcinoma cell lines and postoperative lung adenocarcinoma specimens in our previous experiments. We also found that the elevated level of USP14 was associated with enhancement of proliferation of cancer cells. In this study we are going to explore the effects of endogenous USP14 on proliferation, apoptosis, cell cycle and invasive ability of lung adenocarcinoma cells both in vivo and in vitro. We are also trying to reveal the underlying mechanisms of the effects of USP14 on tumor cells. The degradation of ubiquitinated β-catenin has recently been proved to be inhibited by a series of deubiquitinating enzymes. Since the expression of β-catenin protein was found decreased along with USP14 gene interference, we will explore the correlation between the elevated level of USP14 expression and β-catenin accumulation in lung adenocarcinoma cells. By analysis of large sample of postoperative lung adenocarcinoma specimens we will try to find the possible correlation between USP14 expression and specified clinical features of the patie

英文关键词： lung adenocarcinoma；USP14；β-catenin；deubiquitination；proliferation