https://scholars.lib.ntu.edu.tw/handle/123456789/616013
標題: | Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis | 作者: | Lin, Hsin-Ying Chun-Jung Ko Lo, Tzu-Yu Wu, Shang-Ru Lan, Shao-Wei Huang, Chen-An Lin, Yi-Chin Lin, Hsin-Hsien Tu, Hsin-Fang Lee, Cheng-Fan Hsiao, Pei-Wen HSIANG-PO HUANG MEI-JOU CHEN Chang, Kai-Hsiung MING-SHYUE LEE |
關鍵字: | SERINE-PROTEASE MATRIPTASE-2; UROKINASE PLASMINOGEN-ACTIVATOR; ORPHAN NUCLEAR RECEPTORS; BREAST-CANCER; IN-VITRO; IRON; TMPRSS6; SMAD2; EXPRESSION; PROGNOSIS | 公開日期: | 2022 | 出版社: | SPRINGERNATURE | 卷: | 41 | 期: | 20 | 起(迄)頁: | 2833 | 來源出版物: | Oncogene | 摘要: | Dysregulation 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/616013 | ISSN: | 0950-9232 | DOI: | 10.1038/s41388-022-02303-z |
顯示於: | 生物化學暨分子生物學科研究所 |
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