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)在胚胎血管生成/血管生成中起重要作用，主要通过基因敲除研究得到鉴定。然而，对新生血管的调节，例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，我们用逆转录依赖的聚合酶链式反应、免疫印迹和免疫组织化学方法研究了这些转录因子在人类血管丰富的透明细胞型肾癌中的表达水平和模式。所有转录因子均在肾小管细胞癌血管中表达，其中LMO2、TAL1和ID1具有内皮特异性表达模式。CD31高表达的肾癌组织中这些转录因子的表达也较高。报告实验表明，这些转录因子均激活了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关键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(VEGFR)/血管内皮生长因子受体(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.