Enhanced migration of tissue inhibitor of metalloproteinase overexpressing hepatoma cells is attributed to gelatinases: Relevance to intracellular signaling pathways  

作　　者：Elke Roeb Anja-Katrin Bosserhoff Sabine Hamacher Bettina Jansen Judith Dahmen Sandra Wagner Siegfried Matern 

机构地区：[1]Department of Internal Medicine Ⅲ [2]Institute of Pathology

出　　处：《World Journal of Gastroenterology》2005年第8期1096-1104,共9页世界胃肠病学杂志（英文版）

基　　金：Supported by grants from the Federal Ministry of Education Research of Germany, Deutsche Forschungsgemeinschaft (DFG), and Aachen University

摘　　要：AIM: To study the effect of gelatinases (especially MMP-9) on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells. METHODS: Wild type HepG2 cells, cells stably transfected with TIMP-1 and TIMP-1 antagonist (MMP-9-H401A, a catalytically inactive matrix metalloproteinase (MMP) which still binds and neutralizes TIMP-1) were incubated in Boyden chambers either with or without Galardin (a synthetic inhibitor of MMP-1, -2, -3, -8, -9) or a specific inhibitor of gelatinases. RESULTS: Compared to wild type HepG2 cells, the cells overexpressing TIMP-1 showed 115% migration (P<0.05) and the cells overexpressing MMP-9-H401A showed 62% migration (P<0.01). Galardin reduced cell migration dose dependently in all cases. The gelatinase inhibitor reduced migration in TIMP-1 overexpressing cells predominantly. Furthermore, we examined intracellular signal transduction pathways of TIMP-1-dependent HepG2 cells. TIMP-1 deactivates cell signaling pathways of MMP-2 and MMP-9 involving p38 mitogen-activated protein kinase. Specific blockade of the ERK pathway suppresses gelatinase expression either in the presence or absence of TIMP-1. CONCLUSION: Overexpressing functional TIMP-1-enhanced migration of HepG2-TIMP-l cells depends on enhanced MMP-activity, especially MMP-9.AIM: To study the effect of gelatinases (especially MMP-9)on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells.METHODS: Wild type HepG2 cells, cells stably transfected with TIMP-1 and TIMP-1 antagonist (MMP-9-H401A, a catalytically inactive matrix metalloproteinase (MMP) which still binds and neutralizes TIMP-1) were incubated in Boyden chambers either with or without Galardin (a synthetic inhibitor of MMP-1, -2, -3, -8, -9) or a specific inhibitor of gelatinases.RESULTS: Compared to wild type HepG2 cells, the cells overexpressing TIMP-1 showed 115% migration (P＜0.05)and the cells overexpressing MMP-9-H401A showed 62% migration (P＜0.01). Galardin reduced cell migration dose dependently in all cases. The gelatinase inhibitor reduced migration in TIMP-1 overexpressing cells predominantly.Furthermore, we examined intracellular signal transduction pathways of TIMP-1-dependent HepG2 cells. TIMP-1deactivates cell signaling pathways of MMP-2 and MMP-9involving p38 mitogen-activated protein kinase. Specific blockade of the ERK pathway suppresses gelatinase expression either in the presence or absence of TIMP-1.CONCLUSION: Overexpressing functional TIMP-1-enhanced migration of HepG2-TIMP-1 cells depends on enhanced MMP-activity, especially MMP-9.

关 键 词：HepG2 MMP-2 MMP-9 P38MAPK Galardin GENISTEIN 

分 类 号：R735.7[医药卫生—肿瘤]