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

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.

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。

越来越多的证据表明：FOXC1在肿瘤的发展和转移中发挥着重要的作用。然而，FOXC1在非小细胞肺癌转移中的分子机制尚未完全清楚。我们发现，FOXC1在非小细胞肺癌中的高表达与其不良预后相关，多因素分析表明FOXC1可作为非小细胞肺癌的独立预后因子。体内外实验证实FOXC1高表达可以增强非小细胞肺癌细胞的增殖、侵袭和迁移能力，而沉默FOXC1的表达可以抑制这些生物学能力。我们在此阐述了一种新的FOXC1诱导非小细胞肺癌侵袭和转移的机制。我们发现在非小细胞肺癌中，FOXC1和LOX的表达呈正相关。下调过表达FOXC1的H1650 和H1299细胞可以抑制FOXC1诱导的细胞增殖和侵袭。动物模型也证实，应用LOX抑制剂BAPN可以减少肺转移灶的数目。双荧光素酶和CHIP实验证实FOXC1可以通过直接与LOX启动子结合并激活其转录过程来实现其功能的实现。本研究发现一种新的FOXC1调节非小细胞肺癌侵袭和转移中的机制。这些结果揭示了FOXC1在非小细胞肺癌中的重要作用。FOXC1可作为非小细胞肺癌治疗的潜在靶点。.