Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis

  • Oncogene. 2020 Sep;39(37):5950-5963. doi: 10.1038/s41388-020-01413-w.
Chun-Jung Ko   #  1  2 ,  Ting-Wei Hsu   #  1 ,  Shang-Ru Wu  1 ,  Shao-Wei Lan  1 ,  Ting-Feng Hsiao  3  4 ,  Hsin-Ying Lin  1 ,  Hsin-Hsien Lin  1 ,  Hsin-Fang Tu  1 ,  Cheng-Fan Lee  1 ,  Cheng-Chung Huang  1 ,  Mei-Ju May Chen  5 ,  Pei-Wen Hsiao  6 ,  Hsiang-Po Huang  7 ,  Ming-Shyue Lee  8
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 2. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 4. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
  • 5. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
  • 7. Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 8. Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan. [email protected].
  • # Contributed equally.
PMID: 32778768 DOI: 10.1038/s41388-020-01413-w
Abstract

TMPRSS2 is an important membrane-anchored serine protease involved in human prostate Cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2's cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate Cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate Cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate Cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate Cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.

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