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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 41 Issue 20 Pg. 2833-2845 (05 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35418692 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• DNA-Binding Proteins
• Membrane Proteins
• NR4A3 protein, human
• Plasminogen Activator Inhibitor 1
• Receptors, Steroid
• Receptors, Thyroid Hormone
• Transforming Growth Factor beta1
• Serine Endopeptidases
• matriptase 2

Topics

• 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