title: 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 transcription-polymerase 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.
authors.affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazakim Miyazaki 889-1692, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Betsunoh
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Mukai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Naoki
authors.initials: N
authors.lastname: Minamiguchi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hasui
authors.forename: Yukio
authors.initials: Y
authors.lastname: Osada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D008562:Membrane Glycoproteins; C109148:SPINT2 protein, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C081092:HGF activator; D012697:Serine Endopeptidases; C055645:hepsin; C485595:matriptase