Abstract
We have previously shown that human liver myofibroblasts promote in vitro invasion of human hepatocellular carcinoma (HCC) cells through a hepatocyte growth factor (HGF)/urokinase/plasmin-dependent mechanism. In this study, we demonstrate that myofibroblasts synthesize the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2). Despite the fact that recombinant TFPI-2 readily inhibits plasmin, we show that it potentiates HGF-induced invasion of HCC cells and is capable of inducing invasion on its own. Furthermore, HCC cells stably transfected with a TFPI-2 expression vector became spontaneously invasive. HCC cells express tissue factor and specifically factor VII. Addition of an antibody to factor VII abolished the pro-invasive effect of TFPI-2. We suggest that TFPI-2 induces invasion following binding to a tissue factor-factor VIIa complex preformed on HCC cells. Our data thus demonstrate an original mechanism of cell invasion that may be specific for liver tumor cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Northern
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Carcinoma, Hepatocellular / enzymology*
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Cell Division
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Cell Line
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Cricetinae
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DNA, Complementary / metabolism
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Dose-Response Relationship, Drug
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Factor VII / metabolism
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Fibrinolysin / antagonists & inhibitors
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Fibrinolysin / metabolism
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Gene Library
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Glycoproteins / chemistry
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Glycoproteins / metabolism*
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Humans
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Liver / metabolism
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Liver Neoplasms / enzymology
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MAP Kinase Signaling System
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Invasiveness
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Phosphorylation
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Pregnancy Proteins / chemistry
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Pregnancy Proteins / metabolism*
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Protein Isoforms
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Recombinant Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / metabolism*
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Thromboplastin / metabolism
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Transfection
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Tumor Cells, Cultured
Substances
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DNA, Complementary
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Glycoproteins
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Pregnancy Proteins
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Protein Isoforms
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Recombinant Proteins
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Serine Proteinase Inhibitors
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tissue-factor-pathway inhibitor 2
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Factor VII
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Thromboplastin
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Mitogen-Activated Protein Kinases
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Fibrinolysin