Wu S.-R.Cheng T.-S.Chen W.-C.Shyu H.-Y.Chun-Jung KoHSIANG-PO HUANGTeng C.-H.Lin C.-H.Johnson M.D.Lin C.-Y.MING-SHYUE LEE2022-02-082022-02-0820100002-9440https://www.scopus.com/inward/record.uri?eid=2-s2.0-78650207591&doi=10.2353%2fajpath.2010.100228&partnerID=40&md5=176b766389ce7798bde9f1eaad3fb263https://scholars.lib.ntu.edu.tw/handle/123456789/593877Deregulation of both ErbB-2 signaling and matriptase activity has been associated with human prostate cancer (PCa) progression. In this communication, we investigated the roles of both ErbB-2 signaling in matriptase zymogen activation and matriptase in ErbB-2-induced PCa malignancy. In a human PCa cell progression model, we observed that advanced PCa C-81 LNCaP cells exhibited an aggressive phenotype with increased cell migration and invasion capacity; these cells concurrently showed both enhanced ErbB-2 phosphorylation and increased matriptase zymogen activation compared with parental C-33 LNCaP cells. Moreover, ErbB2 activation, both ligand-dependent (eg, epidermal growth factor treatment) and ligand-independent (eg, overexpression), was able to induce matriptase zymogen activation in this cell line. Inhibition of ErbB-2 activity by either the specific inhibitor, AG825, in epidermal growth factor-treated C-33 LNCaP cells or ErbB-2 knockdown in C-81 LNCaP cells, reduced matriptase activation. These observations were confirmed by similar studies using both DU145 and PC3 cells. Together, these data suggest that ErbB-2 signaling plays an important role in matriptase zymogen activation. ErbB-2-enhanced matriptase activation was suppressed by a phosphatidylinositol 3-kinase inhibitor (ie, LY294002) but not by a MEK inhibitor (ie, PD98059). Suppression of matriptase expression by small hairpin RNA knockdown in ErbB-2-overexpressing LNCaP cells dramatically suppressed cancer cell invasion. In summary, our data indicate that ErbB-2 signaling via the phosphatidylinositol 3-kinase pathway results in up-regulated matriptase zymogen activity, which contributes to PCa cell invasion. Copyright ? American Society for Investigative Pathology.[SDGs]SDG32 (2 amino 3 methoxyphenyl)chromone; 2 morpholino 8 phenylchromone; 5 (2 benzothiazolyl)thiomethyl 4 hydroxy 3 methoxybenzylidenecyanoacetamide; epidermal growth factor receptor 2; matriptase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; article; cancer cell; cancer growth; cancer invasion; cell migration; cell motility; enzyme activation; gene overexpression; human; human cell; phenotype; priority journal; prostate cancer; upregulationjournal article10.2353/ajpath.2010.1002282-s2.0-78650207591