Liver Cancer
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2005; 11(8): 1096-1104
Published online Feb 28, 2005. doi: 10.3748/wjg.v11.i8.1096
Enhanced migration of tissue inhibitor of metalloproteinase overexpressing hepatoma cells is attributed to gelatinases: Relevance to intracellular signaling pathways
Elke Roeb, Anja-Katrin Bosserhoff, Sabine Hamacher, Bettina Jansen, Judith Dahmen, Sandra Wagner, Siegfried Matern
Elke Roeb, Sabine Hamacher, Bettina Jansen, Judith Dahmen, Sandra Wagner, Siegfried Matern, Department of Internal Medicine III, University Hospital RWTH Aachen, Germany
Anja-Katrin Bosserhoff, Institute of Pathology, University of Regensburg, Germany
Author contributions: All authors contributed equally to the work.
Correspondence to: Professor Elke Roeb, Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstr. 30, 52057 Aachen, Germany. eroeb@ukaachen.de
Telephone: +49-241-8089200 Fax: +49-241-8082455
Received: June 24, 2004
Revised: June 27, 2004
Accepted: August 22, 2004
Published online: February 28, 2005
Abstract

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-1 cells depends on enhanced MMP-activity, especially MMP-9.

Keywords: HepG2, MMP-2, MMP-9, p38MAPK, Galardin, Genistein