Hepatocyte growth factor activator inhibitor type-2 (HAI-2)/SPINT2 contributes to invasive growth of oral squamous cell carcinoma cells

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// Koji Yamamoto 1, 2 , Makiko Kawaguchi 1 , Takeshi Shimomura 1 , Aya Izumi 1 , Kazuomi Konari 1 , Arata Honda 3 , Chen-Yong Lin 4 , Michael D. Johnson 4 , Yoshihiro Yamashita 2 , Tsuyoshi Fukushima 1 and Hiroaki Kataoka 1 1 Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 2 Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 3 Institute of Laboratory Animals, Kyoto University Graduate School of Medicine, Kyoto, Japan 4 Lambardi Comprehensive Cancer Center, Georgetown University, School of Medicine, Washington, DC, USA Correspondence to: Hiroaki Kataoka, email: mejina@med.miyazaki-u.ac.jp Keywords: oral squamous cell carcinoma; HAI-2; SPINT2 ; prostasin; HAI-1 Received: October 11, 2017 Accepted: February 01, 2018 Published: February 08, 2018 ABSTRACT Hepatocyte growth factor activator inhibitor (HAI)-1/ SPINT1 and HAI-2/ SPINT2 are membrane-anchored protease inhibitors having homologous Kunitz-type inhibitor domains. They regulate membrane-anchored serine proteases, such as matriptase and prostasin. Whereas HAI-1 suppresses the neoplastic progression of keratinocytes to invasive squamous cell carcinoma (SCC) through matriptase inhibition, the role of HAI-2 in keratinocytes is poorly understood. In vitro homozygous knockout of the SPINT2 gene suppressed the proliferation of two oral SCC (OSCC) lines (SAS and HSC3) but not the growth of a non-tumorigenic keratinocyte line (HaCaT). Reversion of HAI-2 abrogated the growth suppression. Matrigel invasion of both OSCC lines was also suppressed by the loss of HAI-2. The levels of prostasin protein were markedly increased in HAI-2-deficient cells, and knockdown of prostasin alleviated the HAI-2 loss-induced suppression of OSCC cell invasion. Therefore, HAI-2 has a pro-invasive role in OSCC cells through suppression of prostasin. In surgically resected OSCC tissues, HAI-2 immunoreactivity increased along with neoplastic progression, showing intense immunoreactivities in invasive OSCC cells. In summary, HAI-2 is required for invasive growth of OSCC cells and may contribute to OSCC progression.