解析ALDH1A3基因启动子区甲基化调控脑胶质瘤恶性进展的分子机制

项目名称： 解析ALDH1A3基因启动子区甲基化调控脑胶质瘤恶性进展的分子机制

项目编号： No.81201993

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： 张伟

作者单位： 首都医科大学

项目金额： 23万元

中文摘要： 胶质瘤是最常见的颅内肿瘤，侵袭及复发是其预后不良的主要原因。我们前期研究利用全基因组甲基化芯片分析胶质母细胞瘤临床样本，筛选并鉴定出ALDH1A3启动子区甲基化状态与患者临床预后密切相关，但其在脑胶质瘤中的作用机制目前还未见报道。为此，我们提出假说：ALDH1A3启动子区甲基化状态调控基因表达，从而影响胶质瘤细胞恶性进展。为了验证这一假说，我们将通过大规模临床样本、体外细胞系和动物成瘤模型，采用焦磷酸测序、小干扰RNA慢病毒转染、细胞生物学功能检测、酵母双杂交、免疫共沉淀等技术手段，从分子、细胞、组织以及动物整体水平探讨ALDH1A3基因在胶质瘤发生发展中的重要作用，阐明ALDH1A3启动子区甲基化导致基因表达沉默，进而调控胶质瘤恶性进展的分子机制。本研究将从ALDH1A3启动子区甲基化这个新视点为揭示脑胶质瘤的发病机理奠定基础，为脑胶质瘤的分子诊断、预后判断及分子靶向治疗提供新的思路。

中文关键词： 脑胶质瘤；ALDH1A3；分子标记物；间质型；预后

英文摘要： Glioma is the most common form of brain tumor, and invasion and recurrence is the main reason for its poor prognosis. In our previous studies, whole-genome DNA methylation profiling was performed and revealed that the methylation status of ALDH1A3 promoter was associated with clinical prognosis in glioblastoma (GBM) patients. To date, the molecular mechanisms of ALDH1A3 promoter methylation and protein expression in gliomagenesis have not yet been elucidated. Here, we propose a hypothesis that ALDH1A3 gene expression level, which is regulated by its promoter methylation status, may contribute to the malignant phenotype of gliomas and be a potential biomarker of molecular targeted therapy. To verify the above hypothesis, we will analyze the clinical significance of ALDH1A3 in a large number of clinical specimens and explore its functional role in gliomas via a series of molecular biology avenues in vitro and in vivo, such as pyrosequencing, RNAi, cell function assays, yeast two-hybrid system, co-immunoprecipitation, xenograft, et al. In summary, the present study aims to investigate the role of ALDH1A3 promoter methylation and protein expression in gliomagenesis and evaluate the possibility of ALDH1A3 as a potential target for gene therapy.

英文关键词： Glioma；ALDH1A3；Biomarkers；Mesenchymal；Prognosis