FOXC1在非小细胞肺癌血管生成中的作用及其上调VEGF-A表达的分子机制

项目名称： FOXC1在非小细胞肺癌血管生成中的作用及其上调VEGF-A表达的分子机制

项目编号： No.81501989

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： 刘杰

作者单位： 山东大学

项目金额： 18万元

中文摘要： 我们前期研究发现叉头框转录因子C1(FOXC1)在非小细胞肺癌（NSCLC）细胞中高表达，且为NSCLC患者独立预后不良因子，其作用机制尚不明确。FOXC1可促进胚胎时期心脏血管生成，且前期发现在NSCLC组织中，FOXC1高表达组中微血管密度要显著高于FOXC1低表达组，提示FOXC1可能参与NSCLC血管生成。同时也发现其在NSCLC细胞中的表达与血管内皮生长因子-A(VEGF-A)表达显著正相关；过表达或干扰肺癌细胞株中FOXC1的表达后，VEGF-A的mRNA及蛋白表达相应升高或降低。推测FOXC1可介导VEGF-A表达升高参与NSCLC血管生成，促进肿瘤的发生发展。拟采用体外肿瘤细胞/人脐静脉血内皮细胞共培养体系及体内鸡胚绒毛尿囊膜模型，观察FOXC1对NSCLC血管生成的影响，并明确FOXC1介导VEGF-A表达升高的分子机制，为NSCLC新的靶向药物的开发提供实验基础。

中文关键词： 叉头框转录因子C1；血管内皮生长因子A；肺肿瘤；血管生成

英文摘要： In our previous study, we found that forkhead box C1 (FOXC1) was highly expressed in non-small cell lung cancer (NSCLC) and acted as an independent prognostic factor for overall survival in univariate and multivariate analysis. However, the potential mechanisms of FOXC1 in NSCLC development remain unkown. Recent studies showed that FOXC1 was required for vascular development, and in our study a significant association between FOXC1 expression and microvessel density (MVD) was seen , which demonstrated that FOXC1 might promote the angiogenesis in NSCLC. We further found there was a positive correlation between FOXC1 and VEGF-A expression and overexpression of FOXC1 in FOXC1-transfected cell lines exhibited significantly increased VEGF mRNA and protein expression, whereas siRNA-mediated FOXC1 knockdown yielded opposite effects. We hypothesized that FOXC1 transcriptionally regulated VEGF-A expression and promoted the angiogenesis in NSCLC. In this study, we will explore the role of FOXC1 in tumor angigenesis in vitro and in vivo and analyze if it is mediated in VEGF-dependant pattern. Besides, the molecular mechanisms that upregulate VEGF-A expression will be clarified. This may help identify novel and effective targets for malignant NSCLC treatment.

英文关键词： FOXC1;VEGF-A;non-small cell lung cancer;angiogenesis