Chun-Jung KoHuang C.-C.Lin H.-Y.Juan C.-P.Lan S.-W.Shyu H.-Y.Wu S.-R.Hsiao P.-W.HSIANG-PO HUANGCHIA-TUNG SHUNMING-SHYUE LEE2022-02-082022-02-0820150008-5472https://www.scopus.com/inward/record.uri?eid=2-s2.0-84942862103&doi=10.1158%2f0008-5472.CAN-14-3297&partnerID=40&md5=2085bb753ddaaaa44e9f2f5698e5e2f4https://scholars.lib.ntu.edu.tw/handle/123456789/593873Dysregulation of androgen signaling and pericellular proteolysis is necessary for prostate cancer progression, but the links between them are still obscure. In this study, we show how the membrane-anchored serine protease TMPRSS2 stimulates a proteolytic cascade that mediates androgen-induced prostate cancer cell invasion, tumor growth, and metastasis. We found that matriptase serves as a substrate for TMPRSS2 in mediating this proinvasive action of androgens in prostate cancer. Further, we determined that higher levels of TMPRSS2 expression correlate with higher levels of matriptase activation in prostate cancer tissues. Lastly, we found that the ability of TMPRSS2 to promote prostate cancer tumor growth and metastasis was associated with increased matriptase activation and enhanced degradation of extracellular matrix nidogen-1 and laminin β1 in tumor xenografts. In summary, our results establish that TMPRSS2 promotes the growth, invasion, and metastasis of prostate cancer cells via matriptase activation and extracellular matrix disruption, with implications to target these two proteases as a strategy to treat prostate cancer. ? 2015 American Association for Cancer Research.[SDGs]SDG3androgen; entactin; laminin; laminin beta1; matriptase; nidogen 1; serine proteinase; TMPRSS2 protein; unclassified drug; androgen; matriptase; serine proteinase; TMPRSS2 protein, human; animal experiment; animal model; Article; carcinogenesis; cell invasion; controlled study; enzyme activation; extracellular matrix; human; human tissue; in vitro study; in vivo study; male; metastasis potential; mouse; nonhuman; priority journal; prostate cancer; protein analysis; protein degradation; protein expression; signal transduction; tumor growth; tumor invasion; tumor xenograft; animal; cell proliferation; CHO cell line; Cricetulus; drug effects; enzyme activation; extracellular matrix; genetics; hamster; HEK293 cell line; metabolism; metastasis; nude mouse; pathology; physiology; prostate tumor; SCID mouse; tumor cell culture; tumor invasion; upregulation; Androgens; Animals; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Enzyme Activation; Extracellular Matrix; HEK293 Cells; Humans; Male; Mice; Mice, Nude; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Prostatic Neoplasms; Serine Endopeptidases; Tumor Cells, Cultured; Up-Regulationjournal article10.1158/0008-5472.CAN-14-3297260180852-s2.0-84942862103