PTBP1介导的survivinΔEx3过表达调控胶质母细胞瘤微血管增生的机制研究

项目名称： PTBP1介导的survivinΔEx3过表达调控胶质母细胞瘤微血管增生的机制研究

项目编号： No.81201794

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： 黄颖

作者单位： 福建省立医院

项目金额： 23万元

中文摘要： 胶质母细胞瘤是发病率最高的脑部恶性肿瘤，微血管丛状增生是其典型特征，抑制血管生成是胶质母细胞瘤治疗的重要方面。本课题组前期发现胶质母细胞瘤组织及细胞中过表达survivinΔEx3。survivinΔEx3不但具有抗细胞凋亡功能，还参与调控肿瘤血管生成。在胶质母细胞瘤细胞中特异性下调剪接因子PTBP1的表达，导致survivinΔEx3表达量明显降低；结合生物信息学分析结果，我们提出PTBP1参与调控survivinΔEx3的剪接，导致胶质母细胞瘤微血管增生的假说。本课题拟通过RNA剪接模型细胞培养及EMSA和ChIP等实验证实PTBP1通过结合在特定剪接识别位点，参与调控survivinΔEx3的选择性剪接；并拟通过小管形成实验及移植瘤动物模型实验阐明PTBP1介导的survivinΔEx3过表达在胶质母细胞瘤微血管增生方面的意义，旨在为胶质母细胞瘤靶向抑制血管生成提供一个新的靶点。

中文关键词： 剪接调控；PTBP1；survivinΔEx3；选择性剪接；胶质母细胞瘤

英文摘要： Glioblastoma is the most frequent malignant tumor of the central nervous system. Microvascular proliferation is a histopathological hallmark of glioblastoma. Inhibiting angiogenesis would be an important approach for the treatment of glioblastoma. In our previous study, we found the level of survivinΔEx3 was increased in glioblastoma tissues and cell lines. However, the mechanisms underlying the alternative splicing of survivin remain unknown. A number of studies have revealed that survivinΔEx3 not only plays an important role in inhibiting apoptosis, but also takes part in regulating tumor angiogenesis. After downregulated splicing factor PTBP1 expression via specific siRNA in glioblastoma cell line, we found that the level of survivinΔEx3 mRNA was dramatically decreased. Based on bioinformatics analysis of the genome sequence of survivin, we put forward the hypothesis that PTBP1 involves in the regulation of survivinΔEx3 alternative splicing, and PTBP1-mediated survivinΔEx3 over-expression induces microvascular proliferation in glioblastomas. This project aims to confirme that PTBP1 regulates survivinΔEx3 alternative splicing through specific recognition and combination the binding sites, by using specific RNA splicing pathway models cell culture, EMSA and ChIP experiments. This project also intends to clarif

英文关键词： Splicing regulation；PTBP1；SurvivinΔEx3；Alternative splicing；Glioblastoma