Phosphorylation of MET Is Upregulated in Metastatic Sites of Renal Cell Carcinoma: Possible Role of MET and Hepatocyte Growth Factor Activation-Targeted Combined Therapy

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Abstract
Background: Increased expression of MET and hepatocyte growth factor (HGF)-related molecules has been positively correlated with poor prognosis in renal cell carcinoma (RCC). In the current study, the expression and phosphorylation of MET in metastatic RCC (mRCC) are determined by immunohistochemistry, and the therapeutic effect of MET and HGF activation-targeting agents for RCC cell lines is analyzed. Methods: Immunohistochemistry was performed for 76 formalin-fixed paraffin-embedded specimens (primary tumor: 32, metastatic site: 44). The therapeutic effect of capmatinib (MET-I) and SRI-31215 (inhibitor of HGF-activating proteases: HGFA-I) was determined based on the inhibition of MET phosphorylation, cell proliferation, and cell migration in 786-O and caki-1 cell lines. Results: Increased expression and phosphorylation of MET were observed in both primary tumor and metastatic sites; however, phosphorylation was significantly upregulated in metastatic sites (p = 0.0001). In an assay of RCC cell lines, the strongest inhibition of MET phosphorylation, cell proliferation, and migration was confirmed with the combined used of MET-I and HGFA-I. Conclusions: Phosphorylation of MET was significantly upregulated in metastasis, which suggested the importance of downregulation in the treatment of mRCC. Our findings suggest that dual inhibition of MET and HGF activation may offer a promising strategy for mRCC treatment, warranting further clinical validation.
Funding Information
  • Ministry of Education, Science, Sports and Culture (JP22K09506, JP24K19671)

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