Development of novel renal cell carcinoma therapy targeting signal transduction pathways

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It is well known that inactivation of VHL gene predisposes for human clear cell renal carcinoma (CCRC). But details about critical roles of VHL inactivation during tumorigenesis are still unknown. MET protein is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) to regulate cell growth, cell morphology, and cell motility. We demonstrated that MET protein overexpressed in CCRC cells was phosphorylated without HGF/SF. This constitutive phosphorylation of MET protein in CCRC cells was inhibited by the rescue of exogenous wild-type VHL gene without decrease in expression level of MET protein. Interestingly wild-type VHL gene suppressed the phosphorylation of MET protein only under high cell density conditions. Additionally MET protein activated by the inactivation of VHL gene modified the cell adherence including N-cadherin and □-catenin. When activation of MET protein in CCRC cells was inhibited by the MET inhibitor K252a, the growth of CCRC cells in vitro and the tumorigenesis induced by CCRC cells in nude mice were suppressed. From these results we concluded that inactivation of VHL gene induced constitutive phosphorylation of MET protein and modified intercellular adherence structure to trigger the cell growth released from contact inhibition, finally resulting in tumorigenesis. This is one of the mechanisms of CCRC oncogenesis and MET protein has a potential as a molecular target for novel CCRC therapies.