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

被引:35
作者
Ye, Jingjia [1 ,2 ]
Kawaguchi, Makiko [1 ]
Haruyama, Yukihiro [1 ]
Kanemaru, Ai [1 ]
Fukushima, Tsuyoshi [1 ]
Yamamoto, Koji [1 ]
Lin, Chen-Yong [3 ]
Kataoka, Hiroaki [1 ]
机构
[1] Miyazaki Univ, Dept Pathol, Sect Oncopathol & Regenerat Biol, Miyazaki 8891692, Japan
[2] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Clin Res Ctr, Hangzhou 310003, Zhejiang, Peoples R China
[3] Georgetown Univ, Sch Med, Lombardi Comprehens Canc Ctr, Washington, DC USA
关键词
HAI-1; invasion; metastasis; pancreatic cancer; PAR-2; SERINE-PROTEASE; PERICELLULAR ACTIVATION; MESSENGER-RNA; EXPRESSION; HAI-1; MATRIPTASE; RECEPTOR-2; ADENOCARCINOMA; CARCINOMA; INVASION;
D O I
10.1111/cas.12306
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. Invitro 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.
引用
收藏
页码:44 / 51
页数:8
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