title: 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.affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan; Clinical Research Center, The 2nd Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jingjia
authors.initials: J
authors.lastname: Ye
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Haruyama
authors.forename: Ai
authors.initials: A
authors.lastname: Kanemaru
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Chen-Yong
authors.initials: CY
authors.lastname: Lin
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D012697:Serine Endopeptidases; C485595:matriptase
keywords: HAI‐1; PAR‐2; invasion; metastasis; pancreatic cancer