Regulation of neo-vascularization in human renal cell carcinoma by endothelium-specific transcription factors

许多转录因子（LMO2,TAL1,GATA2,ID1，ETS1和HIF2α）在胚胎血管发生/血管生成中起重要作用，主要是通过基因敲除研究确定的。然而，新血管形成的调控，如与恶性肿瘤生长相关的血管生成，仍然不清楚。为了研究这些转录因子对肿瘤血管生成的调控机制，我们采用逆转录酶依赖PCR、western blot或免疫组织化学等方法研究了这些转录因子在透明细胞型肾细胞癌（ccRCC）（人类肿瘤中血管最丰富的肿瘤之一）中的表达水平和表达模式。本文研究的所有转录因子均在ccRCC中与血管相关表达，其中LMO2、TAL1、ID1呈现内皮特异性表达模式。CD31表达越高的RCC，这些转录因子的表达也越高。报告子实验表明，所有这些转录因子都激活了FLK1启动子/增强子。我们的研究表明，一些在胚胎血管生成中起重要作用的转录因子在肿瘤血管中表达，并可能通过激活血管内皮生长因子(VEGF)/VEGF受体（VEGFR）途径发挥作用。

A number of transcription factors (LMO2,TAL1,GATA2,ID1,ETS1,and HIF2α), which play important roles in embryonic vasculogenesis/angiogenesis, have been identified chiefly using a gene knockout study. However, the regulation of neo-vascularization, such as angiogenesis associated with malignant tumor growth, remains obscure. In order to study the regulatory mechanism of tumor angiogenesis by these transcription factors, their expression level and pattern were studied in clear cell type renal cell carcinoma (ccRCC) (one of the most vascular-rich among human cancers) by reverse transcriptase-dependent PCR, western blot, or immunohistochemistry. All the transcription factors studied here were expressed in ccRCC in association with its blood vessels, and, among them, LMO2,TAL1,and ID1 showed endothelium-specific expression patterns. RCC with higher CD31 expression showed higher expression of these transcription factors. Reporter assay demonstrated that all these transcription factors activated FLK1 promoter/enhancer. Our study demonstrates that some of the transcription factors playing essential roles in embryonic angiogenesis are expressed in tumor blood vessels and may function by activating the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway.