The Kunitz Domain I of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cells

• Published in: Scientific reports 2017-11, Vol.7 (1), p.15101-15101, Article 15101
• Main Authors: Wu, Shang-Ru, Teng, Chen-Hsin, Tu, Ya-Ting, Ko, Chun-Jung, Cheng, Tai-Shan, Lan, Shao-Wei, Lin, Hsin-Ying, Lin, Hsin-Hsien, Tu, Hsin-Fang, Hsiao, Pei-Wen, Huang, Hsiang-Po, Chen, Chung-Hsin, Lee, Ming-Shyue
• Format: Article
• Language: English
• Subjects: 119/118; 13/109; 13/89; 14; 14/19; 38; 38/1; 631/337/474; 631/57; 631/67/589/466; 82; 82/83; 9/10; Amino Acid Sequence; Androgens; Animals; Cell activation; Cell Line, Tumor; Cell Movement; Cell surface; Growth factors; HEK293 Cells; Hepatocyte growth factor; Humanities and Social Sciences; Humans; Invasiveness; Male; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice, Inbred BALB C; Motility; multidisciplinary; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Domains; Proteolysis; RNA Interference; Science; Science (multidisciplinary); Sequence Homology, Amino Acid; Serine; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Serine proteinase; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - genetics; Serine Proteinase Inhibitors - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-15415-4

Dysregulation of pericellular proteolysis is often required for tumor invasion and cancer progression. It has been shown that down-regulation of hepatocyte growth factor activator inhibitor-2 (HAI-2) results in activation of matriptase (a membrane-anchored serine protease), human prostate cancer cell motility and tumor growth. In this study, we further characterized if HAI-2 was a cognate inhibitor for matriptase and identified which Kunitz domain of HAI-2 was required for inhibiting matriptase and human prostate cancer cell motility. Our results show that HAI-2 overexpression suppressed matriptase-induced prostate cancer cell motility. We demonstrate that HAI-2 interacts with matriptase on cell surface and inhibits matriptase proteolytic activity. Moreover, cellular HAI-2 harnesses its Kunitz domain 1 (KD1) to inhibit matriptase activation and prostate cancer cell motility although recombinant KD1 and KD2 of HAI-2 both show an inhibitory activity and interaction with matriptase protease domain. The results together indicate that HAI-2 is a cognate inhibitor of matriptase, and KD1 of HAI-2 plays a major role in the inhibition of cellular matritptase activation as well as human prostate cancer invasion.