MACC1 对人脑多形性胶质母细胞瘤血管生成的影响及分子机制

Glioblastoma (GBM) is the most malignant tumors of all the central nervous system tumors. But we have no effective treatment method for GBM currently. One of its important biological features is rich angiogenesis. Vascular endothelial growth factor (VEGF) has the most effect of promoting tumor blood vessels formation. It has been reported that MACC1 could bind to MET promoter. So, it plays a positive role in promoting transcription regulation, proliferation and invasion of GBM. We found that there is a positive correlation between the expression of MACC1 and vascular density in GBM clinical samples. Furthermore, after down-regulation of MACC1 in U87 cell line which is GBM derived, VEGF expression was significantly reduced. It suggests that MACC1 may be involved in the VEGF-induced GBM angiogenesis. But at present, the exact molecular mechanism of MACC1 and angiogenesis is not clear. This project intends to construct GBM cell line of interference and over expression of MACC1, and then clear the effect on angiogenesis of MACC1 in GBM. Research the effect of MACC1 on VEGF transcriptional regulation mode, action sites, and the involved molecular mechanisms. This project would complete the relationship and mechanism between MACC1 and GBM angiogenesis, and provide new therapeutic targets for GBM invasion and angiogenesis properties.

胶质母细胞瘤(GBM)是中枢神经系统恶性程度最高的肿瘤，目前对其缺乏有效的治疗手段；丰富的血管生成是其重要的特征之一，而肿瘤细胞分泌的血管内皮生长因子(VEGF)是促进肿瘤血管生成最为主要的细胞因子。已有研究报道MACC1与MET启动子结合，发挥正转录调控作用，促进GBM的增殖及侵袭。我们发现在GBM临床标本中MACC1的表达与血管密度正相关；且在GBM来源的U87细胞系中下调MACC1后，VEGF显著降低，提示MACC1可能是通过VEGF参与了GBM的血管形成。但MACC1与血管生成关系及所涉及分子机制尚不清楚。本课题拟构建干涉和过表达MACC1的GBM细胞系，明确其对GBM血管生成的影响；研究MACC1对VEGF转录调控作用方式、作用位点，及所涉及的分子机制。本课题拟完成MACC1与GBM血管生成的关系及其机制研究，为针对GBM侵袭和血管生成特性提供新的治疗靶点。