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Elucidation in the mechanism of human renal cell carcinoma cancer growth and micrometastasis with inactivation of VHL

阐明 VHL 失活后人肾细胞癌生长和微转移的机制

基本信息

批准号：
14370515
负责人：
SHUIN Taro
金额：
$ 7.3万
依托单位：
Kochi University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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-14370515/
关键词：
tumor suppressor gene methylation renal cell carcinoma VHL gene VEGF MIRC9 Hypoxia Inducible Factor メチル化 CpG island methylator phenotype VHL Ubiquitin liagase

项目摘要

Since human renal cell carcinoma (RCC) is resistant against chemotherapy or radiation therapy, there is no definitive curable treatment for the advanced RCC or its distant metastasis. Several cytokines shows only minor effect. Human clear cell RCCs compose of 80% of whole human RCCs. It is well known that von Hippel-Lindau (VHL) disease gene is mutated and inactivated in 70% of human clear cell RCCs. VHL protein makes complex with ElonginB & C to VBC complex in normal cells and works as ubiquitin ligase. It ubiquitates hypoxia inducible factor (HIF) at normoxic condition. HIF is degradeted at proteasome. When VHL gene is inactivated, HIF is upregulated at normoxic condition. This condition result in the high level of HIF, thereby overproduction of VEGF or Glucose transporter. That causes in a good condition for human RCCs. However, this condition itself is not sufficient for the explanation of the tumor development for human RCCs. We tried to detect methylated and inactivated possible tumor suppressor genes in human RCCs, which explains tumor development and growth together with inactivation of VHL. Several genes such as RASSF1A, CHFA, CACNA1G, TMS1,Cox2,DAPK, MINT, MINT2,MIRC9,MIRC37 are methylated and inactivated in human clear cell RCCs in Japan at different kind of extent. Similar findings are obtained in human clear cell lines. Therefore it is regarded that inactivation of the VHL gene with these genes are responsible for the development of human RCCs. Several pathways such as, HIF, VEGF, and Elongin are involved for the development and progression of human clear cell RCCs.

由于人肾细胞癌（RCC）对化疗或放射治疗具有抵抗性，因此对于晚期RCC或其远处转移没有确定的可治愈的治疗。几种细胞因子仅显示轻微的作用。人透明细胞RCC占整个人RCC的80%。众所周知，在70%的人透明细胞RCC中，von Hippel-Lindau（VHL）病基因发生突变和失活。VHL蛋白在正常细胞中与ElonginB和C形成复合物，形成VBC复合物，并作为泛素连接酶发挥作用。它在常氧条件下泛素化缺氧诱导因子（HIF）。HIF在蛋白酶体降解。当VHL基因失活时，HIF在常氧条件下上调。这种情况导致高水平的HIF，从而过量产生VEGF或葡萄糖转运蛋白。这使得人类RCC处于良好状态。然而，这种情况本身并不足以解释人类RCC的肿瘤发展。我们试图检测甲基化和失活的人类RCC中可能的抑癌基因，这解释了肿瘤的发展和生长以及VHL的失活。RASSF 1A、CHFA、CACNA 1G、TMS 1、Cox 2、DAPK、MINT、MINT 2、MIRC 9、MIRC 37等基因在日本人透明细胞RCC中存在不同程度的甲基化和失活。在人类透明细胞系中获得了类似的发现。因此，认为VHL基因与这些基因的失活是人类RCC发生的原因。HIF、VEGF和Elongin等多种途径参与了人透明细胞RCC的发生和发展。