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

Cancer Science

Jingjia Ye²  Makiko Kawaguchi²  Yukihiro Haruyama²  Ai Kanemaru²  Tsuyoshi Fukushima²  Koji Yamamoto²  Chen-Yong Lin¹ 

[1] Lombardi Comprehensive Cancer Center, School of Medicine, Georgetown University, Washington, DC, USA;Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan

关键词: HAI‐1;    invasion;    metastasis;    pancreatic cancer;    PAR‐2;   

DOI  :  10.1111/cas.12306

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND   
© 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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