组蛋白甲基转移酶EZH2介导的FHL1基因表观遗传学沉默在口腔鳞癌发生中作用和机制研究

项目名称： 组蛋白甲基转移酶EZH2介导的FHL1基因表观遗传学沉默在口腔鳞癌发生中作用和机制研究

项目编号： No.81202130

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： 曹巍

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 口腔鳞癌代表了一类恶性程度高、具有异质性特点的实体肿瘤。研究已经表明表观遗传学修饰介导的分子表达谱的改变在口腔鳞癌发生、发展中发挥着重要作用。前期实验结果发现，异常高表达的组蛋白甲基转移酶EZH2与口腔鳞癌恶性表型的维持以及口腔癌前病变-白斑的恶性转化密切相关。为了进一步阐明EZH2在口腔颌面头颈鳞癌发生中所涉及的具体分子网络以及其直接靶向的抑癌基因，申请者首先通过使用生物信息学手段，预测FHL1基因是EZH2一个潜在候选的靶基因；接下来通过使用多种分子生物学及生物化学技术，更加合理地证实FHL1基因是EZH2蛋白直接的作用靶点；最后应用基因转导和RNA干扰技术确定FHL1基因在口腔颌面头颈鳞癌发生中发挥的关键作用。研究结果能明确FHL1作为口腔颌面头颈鳞癌新的候选抑癌基因的可能性，为FHL1基因作为口腔颌面头颈鳞癌新的诊断、治疗的靶点提供实验依据和理论基础，具有重要理论意义和潜在应用价值

中文关键词： 口腔鳞癌；抑癌基因；基因芯片；DNA甲基化；组蛋白甲基化

英文摘要： Oral squamous cell carcinoma (OSCC) is widely represented as a heterogeneous tumor with more aggressive phenotype. It was reported that molecular signature alterations based on epigenetic modifications play a critical role in oral squamous cell carcinoma (OSCC) initiation and progression. In the previous study, we showed that up-regualtion of the Polycomb complex histone methytransferase EZH2 is critical to maintain the malignant phenotypes in OSCC and associated significantly with oral squamous cell carcinoma development in patients with oral precancerous tissue-oral leukoplakia(OLP). In order to identify a specific molecular network in which EZH2 involved and the tumor suppressor gene silencing mediated directly by EZH2 in oral squamous cell carcinoma, our group firstly predicts FHL1 gene is a putative and candidate target gene of EZH2 by bioinformatics approach; Then through performing a lot of molecular biology and biochemistry's skills, we reasonably show that FHL1 is a direct target gene of EZH2; Eventually, FHL1 will be identified as a key functional gene in OSCC initiation by FHL1 exogenous overexpression and knock down . The results of this project will provide the possibilty of FHL1 as a novel cadidate tumor suppressor gene in OSCC and provide the rationale of FHL1 as a novel diagnostic, therapeutic ta

英文关键词： OSCC；TSG；gene array；DNA methylation；Histone methylation