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

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.

• Authors: Jingjia Ye, Makiko Kawaguchi, Yukihiro Haruyama, Ai Kanemaru, Tsuyoshi Fukushima, Koji Yamamoto, Chen-Yong Lin, Hiroaki Kataoka
• Journal: Cancer science (Cancer Sci) Vol. 105 Issue 1 Pg. 44-51 (Jan 2014) ISSN: 1349-7006 [Electronic] England
• PMID: 24147538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Oligopeptides
• Proteinase Inhibitory Proteins, Secretory
• SPINT1 protein, human
• seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
• Serine Endopeptidases
• matriptase

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Cell Line, Tumor
• Cell Movement (physiology)
• Heterografts
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Middle Aged
• Neoplasm Invasiveness
• Oligopeptides (genetics, metabolism)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Proteinase Inhibitory Proteins, Secretory (deficiency, genetics, metabolism)
• Serine Endopeptidases (genetics, metabolism)