Lin, Hsin-YingHsin-YingLinChun-Jung KoLo, Tzu-YuTzu-YuLoWu, Shang-RuShang-RuWuLan, Shao-WeiShao-WeiLanHuang, Chen-AnChen-AnHuangLin, Yi-ChinYi-ChinLinLin, Hsin-HsienHsin-HsienLinTu, Hsin-FangHsin-FangTuLee, Cheng-FanCheng-FanLeeHsiao, Pei-WenPei-WenHsiaoHSIANG-PO HUANGMEI-JOU CHENChang, Kai-HsiungKai-HsiungChangMING-SHYUE LEE2022-07-292022-07-2920220950-9232https://scholars.lib.ntu.edu.tw/handle/123456789/616013Dysregulation of pericellular proteolysis is strongly implicated in cancer metastasis through alteration of cell invasion and the microenvironment. Matriptase-2 (MT-2) is a membrane-anchored serine protease which can suppress prostate cancer (PCa) cell invasion. In this study, we showed that MT-2 was down-regulated in PCa and could suppress PCa cell motility, tumor growth, and metastasis. Using microarray and biochemical analysis, we found that MT-2 shifted TGF-β action towards its tumor suppressor function by repressing epithelial-to-mesenchymal transition (EMT) and promoting Smad2 phosphorylation and nuclear accumulation to upregulate two TGF-β1 downstream effectors (p21 and PAI-1), culminating in hindrance of PCa cell motility and malignant growth. Mechanistically, MT-2 could dramatically up-regulate the expression of nuclear receptor NR4A3 via iron metabolism in PCa cells. MT-2-induced NR4A3 further coactivated Smad2 to activate p21 and PAI-1 expression. In addition, NR4A3 functioned as a suppressor of PCa and mediated MT-2 signaling to inhibit PCa tumorigenesis and metastasis. These results together indicate that NR4A3 sustains MT-2 signaling to suppress PCa cell invasion, tumor growth, and metastasis, and serves as a contextual factor for the TGF-β/Smad2 signaling pathway in favor of tumor suppression via promoting p21 and PAI-1 expression.enSERINE-PROTEASE MATRIPTASE-2; UROKINASE PLASMINOGEN-ACTIVATOR; ORPHAN NUCLEAR RECEPTORS; BREAST-CANCER; IN-VITRO; IRON; TMPRSS6; SMAD2; EXPRESSION; PROGNOSIS[SDGs]SDG3journal article10.1038/s41388-022-02303-z354186922-s2.0-85128236356WOS:000783468200003https://scholars.lib.ntu.edu.tw/handle/123456789/611015https://www.scopus.com/inward/record.uri?eid=2-s2.0-85128236356&doi=10.1038%2fs41388-022-02303-z&partnerID=40&md5=a18ec7428875594adcd5fff72a0f1885