Clinical relevance of hepsin and hepatocyte growth factor activator inhibitor type 2 expression in renal cell carcinoma

Abstract

Cell surface proteolysis is important for the generation of bioactive proteins mediating tumor progression. Recent studies suggest that the membrane-anchored cell surface proteinases matriptase and hepsin have significant roles in tumors. We analyzed the expression and clinical relevance of matriptase and hepsin, and their inhibitors hepatocyte growth factor activator inhibitor type 1 (HAI-1) and type 2 (HAI-2) in 66 cases of conventional renal cell carcinomas (RCC). The mRNA level was evaluated in paired samples from tumor and non-tumorous renal tissues by real-time reverse transcriptionpolymerase chain reaction. As matriptase and hepsin potently activate the proform of hepatocyte growth factor (HGF), the expression of HGF and its receptor, c-Met, was also analyzed. Although upregulation of matriptase was observed occasionally in RCC, the expression level was not associated with prognostic parameters. Hepsin was downregulated in RCC, particularly in early stage disease, but upregulated in advanced stages. There was a trend of higher hepsin expression in RCC with distant metastasis, and Kaplan-Meier survival curves showed that high hepsin expression was associated with reduced overall survival (P < 0.01, log-rank test). Moreover, multivariate analysis indicated that hepsin was an independent prognostic factor. Overexpression of HGF or c-Met also showed reduced overall survival. We also observed a tendency of low HAI-2 expression with reduced overall survival and a statistical association between high hepsin and low HAI-2 level. No associations were observed between matriptase and HAI-1 and HAI-2. Our findings suggest that the balance between hepsin and its inhibitor, HAI-2, may have prognostic value in RCC. (Cancer Sci 2007; 98: 491-498) I t is well known that deregulated proteolysis is a hallmark of cancer. Proteolytic activities in the pericellular microenvironment are critically important for cancer cells to enable growth, survival and invasion. Membrane-anchored serine proteinases are a recently emerging group of cell surface enzymes with potential roles in cancer. So far more than 20 enzymes that belong to this group have been reported.(1) Among them, a number of recent studies have indicated that matriptase (also known as membrane-type serine protease 1) and hepsin are involved in malignant progression of various cancers.(1-7) Both matriptase and hepsin are type 2 transmembrane proteins with an extracellular serine proteinase domain, and show enhanced expression in a variety of tumor tissues.(1) Matriptase has been proposed to initiate signaling and proteolytic cascades through its ability to activate pro-urokinase and protease-activated receptor 2, (8,9) and hepsin is thought to be involved in the activation of the coagulation cascade.(10) Moreover, recent studies have revealed that both enzymes efficiently activate the proform of hepatocyte growth factor (HGF), a multifunctional growth factor acting through its high-affinity receptor tyrosine kinase, c-Met. (8,9,11) A significant body of evidence has acc...

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A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

“…Dysregulation of the HGF/c-Met signaling axis can lead to aberrant cell proliferation and drug resistance and promote cell migration, invasive growth, and angiogenesis (3)(4)(5)(6)(7)(8)(9), and is observed in many malignancies, including those of the pancreas, lung, stomach, breast, and kidney (3,5,(10)(11)(12)(13)(14)(15)(16).…”

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