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.
