FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells.
FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells.
复制标题
DOI：
10.1158/0008-5472.can-08-1968
复制
发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Huang, Suyun
中科院分区：
文献类型：
--
作者：
Zhang, Yujian;Zhang, Nu;Dai, Bingbing;Liu, Mingguang;Sawaya, Raymond;Xie, Keping;Huang, Suyun
我们先前发现FoxM1B在人脑胶质母细胞瘤中过表达，在间变性星形细胞瘤细胞中强制表达FoxM1B会导致裸鼠体内形成高血管生成的胶质母细胞瘤。然而，FoxM1B促进胶质瘤血管生成的分子机制目前尚不清楚。在本研究中，我们发现血管内皮生长因子(VEGF)是FoxM1B的直接转录靶点。FoxM1B过表达增加了胶质瘤细胞中VEGF的表达，而阻断FOXM1的表达则抑制了VEGF的表达。FOXM1基因导入胶质瘤细胞后直接激活了血管内皮生长因子启动子，而FOXM1-siRNA抑制FOXM1的表达则抑制了血管内皮生长因子启动子的激活。我们在血管内皮生长因子启动子中发现了两个与FOXM1蛋白特异结合的FOXM1结合位点。这些FOXM1结合位点的突变显著降低了血管内皮生长因子启动子的活性。此外，FOXM1过表达增加，抑制FOXM1表达抑制了胶质瘤细胞的血管生成能力。最后，59例人GBM标本的免疫组织化学分析也显示FOXM1的过度表达和VEGF的表达升高之间存在显著的相关性。我们的发现为FOXM1通过促进血管内皮生长因子基因转录从而促进肿瘤血管生成而促进胶质瘤进展提供了临床和机制证据。
We previously found that FoxM1B is overexpressed in human glioblastomas (GBMs) and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly angiogenic GBM in nude mice. However, the molecular mechanisms by which FoxM1B enhances glioma angiogenesis are currently unknown. In this study, we found that vascular endothelial growth factor (VEGF) is a direct transcriptional target of FoxM1B. FoxM1B overexpression increased VEGF expression, while blockade of FoxM1 expression suppressed VEGF expression in glioma cells. Transfection of FoxM1 into glioma cells directly activated the VEGF promoter, and inhibition of FoxM1 expression by FoxM1-siRNA suppressed VEGF promoter activation. We identified two FoxM1-binding sites in the VEGF promoter that specifically bound to the FoxM1 protein. Mutation of these FoxM1-binding sites significantly attenuated VEGF promoter activity. Furthermore, FoxM1 overexpression increased and inhibition of FoxM1 expression suppressed the angiogenic ability of glioma cells. Finally, an immunohistochemical analysis of 59 human GBM specimens also showed a significant correlation between FoxM1 overexpression and elevated VEGF expression. Our findings provide both clinical and mechanistic evidence that FoxM1 contributes to glioma progression by enhancing VEGF gene transcription and thus tumor angiogenesis.