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

由于人类肾细胞癌（RCC）对化疗或放疗具有耐药性，对于晚期肾细胞癌或其远处转移尚无明确的可治愈的治疗方法。几种细胞因子仅显示轻微影响。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长链蛋白b和C合成VBC复合物，起泛素连接酶的作用。它在常氧条件下泛在缺氧诱导因子（HIF）。HIF在蛋白酶体上被降解。当VHL基因失活时，HIF在常氧条件下上调。这种情况导致HIF水平升高，从而导致VEGF或葡萄糖转运蛋白的过量产生。这使得人类rcc处于良好的状态。然而，这种情况本身并不足以解释人类rcc的肿瘤发展。我们试图在人类rcc中检测甲基化和失活的可能的肿瘤抑制基因，这解释了肿瘤的发生和生长以及VHL的失活。RASSF1A、CHFA、CACNA1G、TMS1、Cox2、DAPK、MINT、MINT2、MIRC9、MIRC37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也得到了类似的发现。因此，我们认为这些基因的VHL基因失活是导致人类rcc发生的原因。HIF、VEGF和伸长素等多种途径参与了人类透明细胞rcc的发生和发展。

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.