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

Oncogene volume 41, pages 2833–2845 (2022)Cite this article

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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.

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Fig. 1: MT-2 downregulation in PCa tissues and MT-2-suppresses PCa cell motility, tumor growth, and metastasis.
Fig. 2: MT-2 suppresses TGF-β1-induces EMT and PC3 cell invasion.
Fig. 3: MT-2-altered the effect of TGF-β1 on Smad2 phosphorylation, PCa cell colony formation, and invasion, as well as the expression of p21 and PAI-1.
Fig. 4: Identification of NR4A3, an important transcription factor for MT-2 that alters PCa cell response to TGF-β with respect to EMT, PCa colony formation, and invasion.
Fig. 5: NR4A3 enhanced the phosphorylation levels of nuclear Smad2 and TGF-β1-induced p21 and PAI-1 expression.
Fig. 6: Involvement of iron in MT-2 action on NR4A3 expression and PCa cell invasion.
Fig. 7: NR4A3 mediated MT-2-suppressed PCa tumor growth and metastasis.
Fig. 8: Scheme of MT-2-shifted TGF-β action toward suppression of PCa progression.

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Acknowledgements

We appreciate the service of the First Core Laboratory of National Taiwan University College of Medicine. We thank the Laboratory Animal Core Facility (ABRC, Academia Sinica) for their services and Ms. Miranda Loney (Editor, ABRC) for critical suggestions for editing this article. This study was supported by National Health Research Institutes grants NHRI-EX106-10401BI and NHRI-EX109-10725BI, Ministry of Science and Technology grants MOST 104-2320-B-002-044-MY3, MOST 105-2911-I-002-521, MOST 106-2320-B-002-046-MY3 and MOST 108-2320-B-002-024-MY3, MOST 110-2320-B-002-067-MY3, National Taiwan University grants NTU105R89612, NTU107L890504 and NTU110L893503 to M.S. Lee, and NTUH Grant UN110-029 to M.J. Chen and M.S. Lee.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC

    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 & Ming-Shyue Lee

  2. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC

    Pei-Wen Hsiao

  3. Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC

    Hsiang-Po Huang

  4. Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan, ROC

    Mei-Jou Chen

  5. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC

    Kai-Hsiung Chang

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Contributions

HYL executed this study and wrote the manuscript. CJK, SRW, and SWL provided experimental skills consultation. TYL and YCL performed the TCGA bioinformatics analysis. CAH, HHL, HPH, and PWH assisted animal studies. HFT and CFL provided the materials for in vitro assay. MJC and KHC provided technique consultation. MSL supervised the study and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ming-Shyue Lee.

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Lin, HY., Ko, CJ., Lo, TY. et al. Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis. Oncogene 41, 2833–2845 (2022). https://doi.org/10.1038/s41388-022-02303-z

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