CEBPD作为缺氧调控分子网络关键节点促进胶质瘤抗血管治疗耐药性的机制研究

项目名称： CEBPD作为缺氧调控分子网络关键节点促进胶质瘤抗血管治疗耐药性的机制研究

项目编号： No.81502143

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 毛星刚

作者单位： 中国人民解放军第四军医大学

项目金额： 18万元

中文摘要： 抗血管发生药物是近年来唯一获得FDA批准用于胶质瘤治疗的新型药物。然而，抗血管治疗会导致胶质瘤耐药性产生及浸润性进展，这与抗血管治疗引发的肿瘤缺氧反应密切相关。缺氧调控的大量分子形成一复杂网络，以此网络关键节点为治疗靶点从而抑制缺氧反应具有重要的理论价值与应用前景。我们通过对胶质瘤干细胞（GSC）缺氧调控分子网络的生物信息学分析，发现转录激活因子CEBPD是此网络关键节点。进一步研究证实，CEBPD在胶质瘤高表达，且表达高者预后差，其表达水平与多个血管发生因子正相关；CEBPD正向调控GSC增殖。基于这些发现，本项目将深入研究CEBPD在GSC缺氧调控分子网络中的作用，阐明在缺氧及使用抗血管药物的情况下，该分子通过缺氧分子网络促进胶质瘤血管发生、耐药性产生、浸润性进展的作用机制，为探索以抗缺氧反应为目标、以CEBPD为靶点，提高胶质瘤抗血管治疗效果、避免耐药性产生的新策略奠定基础。

中文关键词： 抗血管治疗耐药；胶质瘤母细胞瘤；CEBPD；缺氧；分子网络

英文摘要： Anti-angiogenesis therapy was the only type of novel drugs that are approved by FDA for treatment of gliomas in recent years. However, anti-angiogenesis therapy can induce drug resistance and progressed invasion growth of gliomas, which is closely related to hypoxia induced by anti-angiogenesis therapy. Hypoxia regulates a lot of responsive genes which form a complex molecular network. Therefore, it would be important for theoretical research and clinical practice to find key points of this network as therapeutic target. Our bioinformatics analysis suggested that transcriptional activator CEBPD is a critical point for the hypoxia regulated molecular network in glioma stem like cells (GSCs). Our further studies demonstrated that CEBPD was over-expressed in gliomas and high CEBPD expression predicted poor prognosis. The expression levels of CEBPD was positively correlated with that of several angiogenesis factors. In addition, CEBPD positively regulated the proliferation of GSCs. Based on these findings, the current project will focus to explore the roles of CEBPD in the hypoxia regulated network. We would study the underlying mechanisms of CEBPD induced angiogenesis, drug resistance and progressed invasion growth of gliomas through the hypoxia regulated molecular network, under the conditions of hypoxia and/or administration of anti-angiogenesis agent. The project will provide foundations for establishing novel therapeutic strategies against hypoxia by targeting CEBPD, which would strengthen the therapeutic effect of anti-angiogenesis agent and avoid induction of drug resistance.

英文关键词： resistance to antiangiogenesis therapy;glioblastoma;CEBPD;hypoxia;molecular network