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HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase

Oncogene volume 33, pages 4643–4652 (2014)Cite this article

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Abstract

Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and metastasis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 (HAI-2) in prostate cancer (PCa) cell migration, invasion, tumorigenicity and metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E<N1<N2). In this series of cells, the expression of HAI-2 but not HAI-1 was significantly decreased throughout the progression and occurred in parallel with increased activation of matriptase. The expression level and activity of matriptase increased whereas the HAI-2 protein level decreased over the course of orthotopic tumor growth in mice, which was consistent with the immunohistochemical profiles of matriptase and HAI-2 in archival PCa specimens. Knockdown of matriptase reduced the PCa cell invasion induced by HAI-2 knockdown. HAI-2 overexpression or matriptase silencing in N2 cells downregulated matriptase activity and significantly decreased tumorigenicity and metastatic capability in orthotopically xenografted mice. These results suggest that during the progression of human PCa, matriptase activity is primarily controlled by HAI-2 expression. The imbalance between HAI-2 and matriptase expression led to matriptase activation, thereby increasing cell migration, invasion, tumorigenicity and metastasis.

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Acknowledgements

This study was supported by Taiwan National Health Research Institutes Grants NHRI-EX101-9909BC and NHRI-EX102-9909BC, Taiwan National Science Council Grants NSC 97-2320-B-002-052-MY3, NSC 100-2628-B-002-004-MY4 and NSC 101-2324-B-002-015, the Frontier and Innovative Research Grant of National Taiwan University 98R0305 and National Taiwan University Cutting-Edge Steering Research Project 10R71602C4 to M-S Lee; Postdoctoral Fellowship from the Aim for Top University Program, National Taiwan University, to T-S Cheng; and grants from the National Science Council, Taiwan (NSC 98-2320-B-001-018-MY3), financial and instrumental support from the Agricultural Biotechnology Research Center and Academia Sinica awarded to P-W Hsiao. We are also grateful to Miranda Loney (Editor, ABRC) for critical suggestions editing this article.

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  1. C-H Tsai and C-H Teng: These authors contributed equally to this work.

Authors and Affiliations

  1. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan

    C-H Tsai, S-F Tzeng & P-W Hsiao

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

    C-H Teng, Y-T Tu, T-S Cheng, S-R Wu, C-J Ko, H-Y Shyu, S-W Lan & M-S Lee

  3. Investigation Bureau, Ministry of Justice, Taipei, Taiwan

    H-Y Shyu

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

    H-P Huang

  5. Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    M D Johnson & C-Y Lin

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Tsai, CH., Teng, CH., Tu, YT. et al. HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase. Oncogene 33, 4643–4652 (2014). https://doi.org/10.1038/onc.2013.412

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