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

Chun-Jung Ko, Ting-Wei Hsu, Shang-Ru Wu, Shao-Wei Lan, Ting-Feng Hsiao, Hsin-Ying Lin, Hsin-Hsien Lin, Hsin-Fang Tu, Cheng-Fan Lee, Cheng-Chung Huang, Mei-Ju May Chen, Pei-Wen Hsiao, Hsiang-Po Huang, Ming-Shyue Lee

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5950-5963
Number of pages14
JournalOncogene
Volume39
Issue number37
DOIs
Publication statusPublished - Aug 10 2020
Externally publishedYes

Keywords

  • Animals
  • Carrier Proteins/metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Heterografts
  • Humans
  • Male
  • Membrane Glycoproteins/chemistry
  • Neoplasm Invasiveness
  • Prostatic Neoplasms/etiology
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Proteinase Inhibitory Proteins, Secretory/metabolism
  • Proteolysis
  • Serine Endopeptidases/metabolism

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