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

• Published in: Cancer science 2014-01, Vol.105 (1), p.44-51
• Main Authors: Ye, Jingjia, Kawaguchi, Makiko, Haruyama, Yukihiro, Kanemaru, Ai, Fukushima, Tsuyoshi, Yamamoto, Koji, Lin, Chen‐Yong, Kataoka, Hiroaki
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Animals; Biological activity; Cell Line, Tumor; Cell migration; Cell Movement - physiology; Cell surface; Doxycycline; Gene expression; Growth factors; HAI‐1; Hepatocyte growth factor; Heterografts; Humans; invasion; Invasiveness; Male; Medical prognosis; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Oligopeptides - genetics; Oligopeptides - metabolism; Original; Pancreas transplantation; Pancreatic cancer; Pancreatic islet transplantation; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PAR‐2; Peptides; Proteinase inhibitors; Proteinase Inhibitory Proteins, Secretory - deficiency; Proteinase Inhibitory Proteins, Secretory - genetics; Proteinase Inhibitory Proteins, Secretory - metabolism; Proteins; Serine; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Serine proteinase; Xenografts
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12306

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. HAI‐1 suppresses invasion and metastasis of human pancreatic cancer cells.