Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model

Authors

  • Jingjia Ye,

    1. Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
    2. Clinical Research Center, The 2nd Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, China
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  • Makiko Kawaguchi,

    1. Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
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  • Yukihiro Haruyama,

    1. Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
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  • Ai Kanemaru,

    1. Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
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  • Tsuyoshi Fukushima,

    1. Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
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  • Koji Yamamoto,

    1. Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
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  • Chen-Yong Lin,

    1. Lombardi Comprehensive Cancer Center, School of Medicine, Georgetown University, Washington, DC, USA
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  • Hiroaki Kataoka

    Corresponding author
    1. Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
    • Hiroaki Kataoka, Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki 889-1692, Japan.

      Tel: +81-985-852809; Fax: +81-985-856003;

      E-mail: mejina@med.miyazaki-u.ac.jp

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Abstract

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine protease inhibitor that is expressed on the surface of epithelial and carcinoma cells. On the cell surface, HAI-1 regulates membrane-anchored serine proteases, with matriptase being the most critical target. Matriptase is involved in pericellular processing of biologically active molecules, including protease-activated receptor-2 (PAR-2). Previously we reported that S2-CP8 cells, a metastatic variant of the SUIT-2 human pancreatic adenocarcinoma cell line, showed markedly decreased HAI-1 expression. To assess the significance of HAI-1 loss in invasion and spontaneous metastasis of S2-CP8 cells, we established stable S2-CP8 sublines that expressed HAI-1 under the control of a tetracycline-regulated promoter. In vitro migration and invasion assays revealed inhibitory effects of HAI-1 on S2-CP8 cell migration and invasion. Matriptase activity was suppressed by the expression of HAI-1. As the enhanced invasiveness in the absence of HAI-1 was alleviated by knockdown of matriptase by 81% and of PAR-2 completely, and PAR-2 antagonist also suppressed the invasion, matriptase-mediated PAR-2 activation is involved in HAI-1 loss-induced invasion of S2-CP8 cells. We then analyzed the effect of HAI-1 expression on metastasis of S2-CP8 cells in vivo using a nude mouse orthotopic xenograft model. Although approximately 50% of the control mice developed distant metastasis, mice treated with doxycycline to induce HAI-1 expression did not develop metastasis. These data indicate that HAI-1 loss contributes to invasion and dissemination of a highly metastatic subline of SUIT-2, suggesting crucial roles for the balance of pericellular serine proteases/inhibitors in pancreatic cancer progression.

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