Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model.
Bottom Line: 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.In vitro migration and invasion assays revealed inhibitory effects of HAI-1 on S2-CP8 cell migration and invasion.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.
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.Show MeSH
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Mentions: As S2-CP8 is a metastatic subline, we examined the effect of Tet-induced HAI-1 overexpression on cellular migration and invasion in vitro. As shown in Figure2a, migratory activity was suppressed by the HAI-1 expression. Then, a Matrigel invasion assay was performed. Judging by the number of invaded cells after 24, 48 and 72 h of incubation, S2-CP8 cell invasion was clearly delayed by Tet-induced HAI-1 expression (Fig.2b). Twenty-four hours after plating of S2-CP8_HAI-1tet#1 cells, the number of cells that had migrated was approximately four times higher in the absence of Tet compared to Tet-treated cells. The number of invaded cells was similar after 72 h of incubation, which may be due to the higher growth rate of Tet-treated cells compared to untreated cells (Fig.1c) or the saturation of cells on the lower filter area. Another clone, S2-CP8_HAI-1tet#2, also showed decreased invasiveness in response to Tet treatment (Fig.2c). To further confirm the suppressive role of HAI-1 on invasion of pancreatic cancer cells, we examined the effect of HAI-1 KD on Matrigel invasion of another human pancreatic cancer cell line, AsPC1. While AsPC1 cells were less invasive compared to S2-CP8 cells, transient transfection of siRNA that knocked down HAI-1 expression resulted in enhanced Matrigel invasion (Fig.2d). These data indicate a potentially suppressive role for HAI-1 in the invasiveness of pancreatic cancer cells.
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.