Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis

Hsin-Ying Lin, Chun-Jung Ko, Tzu-Yu Lo, Shang-Ru Wu, Shao-Wei Lan, Chen-An Huang, Yi-Chin Lin, Hsin-Hsien Lin, Hsin-Fang Tu, Cheng-Fan Lee, Pei-Wen Hsiao, Hsiang-Po Huang, Mei-Jou Chen, Kai-Hsiung Chang, Ming-Shyue Lee

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2833-2845
Number of pages13
JournalOncogene
Volume41
Issue number20
DOIs
Publication statusPublished - May 2022

Keywords

  • Cell Line, Tumor
  • Cell Movement
  • DNA-Binding Proteins/metabolism
  • Epithelial-Mesenchymal Transition
  • Humans
  • Male
  • Membrane Proteins/metabolism
  • Neoplasm Invasiveness
  • Plasminogen Activator Inhibitor 1
  • Prostate/pathology
  • Prostatic Neoplasms/pathology
  • Receptors, Steroid/metabolism
  • Receptors, Thyroid Hormone/metabolism
  • Serine Endopeptidases/metabolism
  • Transforming Growth Factor beta1/metabolism
  • Tumor Microenvironment

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