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

内皮特异性转录因子对人肾细胞癌新生血管形成的调节

• 批准号: 14571497
• 负责人: KAMOTO Toshiyuki
• 金额: $ 1.86万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571497/
• 关键词: renal cell carcinoma; neovasculization; LMO2; VEGF

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.

许多在胚胎血管发生/血管生成中起重要作用的转录因子（LMO 2、TAL 1、GATA 2、ID 1、ETS 1和HIF 2 α）主要通过基因敲除研究来鉴定。然而，新血管形成的调节，如与恶性肿瘤生长相关的血管生成，仍然是模糊的。为了研究这些转录因子对肿瘤血管生成的调节机制，通过逆转录酶依赖性PCR、蛋白质印迹或免疫组织化学研究了它们在透明细胞型肾细胞癌（ccRCC）（人类癌症中血管最丰富的癌症之一）中的表达水平和模式。本文研究的所有转录因子在ccRCC中与其血管相关地表达，并且其中，LMO 2、TAL 1和ID 1显示内皮特异性表达模式。CD 31高表达的肾细胞癌显示这些转录因子的高表达。报告基因分析表明这些转录因子均激活FLK 1启动子/增强子。我们的研究表明，一些在胚胎血管生成中发挥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）/血管内皮生长因子受体（VEGFR）途径发挥作用。