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Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

Hepatocyte growth factor (HGF) plays an important role in cancer progression via phosphorylation of MET (c-met proto-oncogene product, receptor of HGF). HGF-zymogen (pro-HGF) must be processed for activation by HGF activators including matriptase, which is a type II transmembrane serine protease and the most efficient activator. The enzymatic activity is tightly regulated by HGF activator inhibitors (HAIs). Dysregulated pro-HGF activation (with upregulated MET phosphorylation) is reported to promote cancer progression in various cancers. We retrospectively analyzed the expression of matriptase, phosphorylated-MET (phospho-MET) and HAI-1 in tumor specimens obtained from patients with invasive bladder cancer by immunohistochemistry. High expression of phospho-MET and increased expression of matriptase were significantly associated with poor prognosis, and high matriptase/low HAI-1 expression showed poorer prognosis. Furthermore, high expression of matriptase tended to correlate with phosphorylation of MET. Increased expression of matriptase may induce the ligand-dependent activation of MET, which leads to poor prognosis in patients with invasive bladder cancer.