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.

Background: The function of hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 in bladder cancer has not been well evaluated. In a previous study, we reported upregulated MET phosphorylation and decreased expression of HAI-1 in bladder cancer as poor prognostic factors. In this study, we analyzed the therapeutic effect of HAI-1 and HAI-2 on bladder cancer cells through the inhibition of MET phosphorylation. Methods: We established stable HAI-1 and HAI-2 overexpression KU-1 cell lines (HAI-1 OE and HAI-2 OE) and HAIs knockdown T24 cell lines (HAI-1 KD and HAI-2 KD). These cell lines were used for cell proliferation, migration, and invasion assay. Next, the cell lines were injected with human fibroblasts subcutaneously in mice, and inhibition of growth was evaluated. Result: Significant inhibition in cancer cell proliferation, motility, and invasiveness was observed in HAI-1 OE and HAI-2 OE compared with the mock in the presence of HGF zymogen, whereas significant upregulation in cancer cell proliferation, motility, and invasiveness was observed in HAI-1 KD and HAI-2 KD cells. In vivo analysis showed significant inhibition of cancer cell growth in HAI-1 OE. Although a tendency toward the inhibition of growth was observed in HAI-2 OE, statistical significance was not achieved. Phosphorylation of MET in cancer tissues was downregulated in both cell lines. Conclusions: HAI-1 may have the therapeutic potential to reduce the growth of bladder cancer through the inhibition of MET phosphorylation.