Research Papers:

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

Koji Yamamoto, Makiko Kawaguchi, Takeshi Shimomura, Aya Izumi, Kazuomi Konari, Arata Honda, Chen-Yong Lin, Michael D. Johnson, Yoshihiro Yamashita, Tsuyoshi Fukushima and Hiroaki Kataoka _

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Oncotarget. 2018; 9:11691-11706. https://doi.org/10.18632/oncotarget.24450

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Koji Yamamoto1,2, Makiko Kawaguchi1, Takeshi Shimomura1, Aya Izumi1, Kazuomi Konari1, Arata Honda3, Chen-Yong Lin4, Michael D. Johnson4, Yoshihiro Yamashita2, Tsuyoshi Fukushima1 and Hiroaki Kataoka1

1Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

2Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

3Institute of Laboratory Animals, Kyoto University Graduate School of Medicine, Kyoto, Japan

4Lambardi Comprehensive Cancer Center, Georgetown University, School of Medicine, Washington, DC, USA

Correspondence to:

Hiroaki Kataoka, email: [email protected]

Keywords: oral squamous cell carcinoma; HAI-2; SPINT2; prostasin; HAI-1

Received: October 11, 2017     Accepted: February 01, 2018     Published: February 08, 2018


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.

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