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

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.

SUBMITTER: Roeb E

PROVIDER: S-EPMC4250697 | biostudies-literature | 2005 Feb

REPOSITORIES: biostudies-literature

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

Roeb Elke E Bosserhoff Anja-Katrin AK Hamacher Sabine S Jansen Bettina B Dahmen Judith J Wagner Sandra S Matern Siegfried S

World journal of gastroenterology 20050201 8

<h4>Aim</h4>To study the effect of gelatinases (especially MMP-9) on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells.<h4>Methods</h4>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 in ...[more]

PMID: 15754388

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Project description:BackgroundAlthough hypoxia is known to promote hepatoma cell invasion and migration, little is known regarding the molecular mechanisms of this process. Our previous research showed that loss of Tg737 is associated with hepatoma cell invasion and migration; therefore, we hypothesized that the Tg737 signal might be required for hypoxia-enhanced invasion and migration.MethodsWe established in vitro normoxic or hypoxic models to investigate the role of Tg737 in the hypoxia-enhanced invasion and migration of hepatoma cells. The hepatoma cell lines HepG2 and MHCC97-H were subjected to normoxic or hypoxic conditions, and the cell adhesion, invasion, and migration capabilities were tested. The expression of Tg737 under normoxia or hypoxia was detected using western blot assays; cell viability was determined using flow cytometry. Furthermore, we created HepG2 and MHCC97-H cells that over expressed Tg737 prior to incubation under hypoxia and investigated their metastatic characteristics. Finally, we analyzed the involvement of critical molecular events known to regulate invasion and migration.ResultsIn this study, Tg737 expression was significantly inhibited in HepG2 and MHCC97-H cells following exposure to hypoxia. The down regulation of Tg737 expression corresponded to significantly decreased adhesion and increased invasion and migration. Hypoxia also decreased the expression/secretion of polycystin-1, increased the secretion of interleukin-8 (IL-8), and increased the levels of active and total transforming growth factor β 1 (TGF-β1), critical regulators of cell invasion and migration. Moreover, the decrease in adhesiveness and the increase in the invasive and migratory capacities of hypoxia-treated hepatoma cells were attenuated by pcDNA3.1-Tg737 transfection prior to hypoxia. Finally, following the up regulation of Tg737, the expression/secretion of polycystin-1 increased, and the secretion of IL-8 and the levels of active and total TGF-β1 decreased correspondingly.ConclusionsThese data provide evidence that Tg737 contributes to hypoxia-induced invasion and migration, partially through the polycystin-1, IL-8, and TGF-β1 pathway. Taken together, this work suggests that Tg737 is involved in the invasion and migration of hepatoma cells under hypoxia, with the involvement of the polycystin-1, IL-8, and TGF-β1 signaling pathway. Tg737 is a potential therapeutic target for inhibiting the high invasion and migration potential of hepatoma cells in hypoxic regions.

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

Publications

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

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