Inactivation of von Hippel-Lindau gene induces constitutive phosphorylation of MET protein in clear cell renal carcinoma.
It is well known that inactivation of von Hippel-Lindau (VHL) gene predisposes for human clear cell renal carcinoma (CCRC). However, 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), which regulates cell growth, cell morphology, and cell motility. We showed 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 a 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 cell adherence, including N-cadherin and beta-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 potential as a molecular target for novel CCRC therapies.
Departments of Urology and Molecular Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama 236-0004, Japan. nakaigan@med.yokohama-cu.ac.jp
Noboru
N
Nakaigawa
Masahiro
M
Yao
Masaya
M
Baba
Shingo
S
Kato
Takeshi
T
Kishida
Keiko
K
Hattori
Yoji
Y
Nagashima
Yoshinobu
Y
Kubota
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C497446:VHL protein, human