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Hepatocyte growth factor stimulates expression of plasminogen activator
inhibitor type 1 and tissue factor in HepG2 cells
J Wojta, T Nakamura, A Fabry, P Hufnagl, R Beckmann, K McGrath and BR Binder
Department of Medical Physiology, University of Vienna, Austria.
HGF is a powerful mitogen for both rat and human hepatocytes, epithelial
cells and endothelial cells in vitro, and is angiogenic in vivo. It has
considerable homology with plasminogen and has been shown to upregulate
urokinase-type plasminogen activator (u-PA) in endothelial cells as well as
u-PA and its receptor in kidney epithelial cells. In this study, we report
that human recombinant HGF stimulates expression of plasminogen activator
inhibitor type 1 (PAI-1) and tissue factor (TF) in the human hepatoma cell
line HepG2. PAI-1 antigen as determined by a specific enzyme-linked
immunosorbent assay increased up to threefold in conditioned media of
HepG2. This increase was dose dependent with maximum stimulation achieved
with a concentration of 50 ng/mL of hepatocyte growth factor (HGF). PAI-1
antigen also increased up to fourfold in the extracellular matrix in HGF
treated HepG2. The production of the PAI-1 binding protein vitronectin (Vn)
was not affected by HGF. In contrast, TF activity in HepG2 treated with HGF
increased up to twofold. As determined by Northern blotting, PAI-1 and
TF-specific mRNA were increased significantly in the presence of HGF,
whereas Vn mRNA was not affected. The increase in PAI-1 and TF mRNA was
also seen when HepG2 were incubated with HGF in the presence of
cycloheximide, thereby indicating that de novo protein synthesis is not
required to mediate the effect. u-PA could be detected neither in
unstimulated or HGF-stimulated HepG2 cells on the antigen level nor on the
mRNA level. In conclusion, our data give evidence that HGF, in addition to
its proliferative effect for different cell types, is also involved in the
local regulation of fibrinolysis and coagulation. One could speculate that
HGF might modulate processes requiring matrix degradation by increasing the
expression of the protease u-PA in one cell type and by upregulating the
expression of the serine protease inhibitor PAI-1 in a different cell type.
Because u-PA has been shown to activate latent HGF to the active form, it
could furthermore be speculated that by upregulating PAI-1, which in turn
could inhibit u- PA, HGF might regulate its own activation.
Volume 84,
Issue 1,
pp. 151-157,
07/01/1994
Copyright © 1994 by The American Society of Hematology
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