Paradoxical pro-invasive effect of the serine proteinase inhibitor tissue factor pathway inhibitor-2 on human hepatocellular carcinoma cells.
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.
Neaud
V
V
Groupe de Recherches pour l'Etude du Foie, INSERM E9917, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France.
Hisaka
T
T
Monvoisin
A
A
Bedin
C
C
Balabaud
C
C
Foster
D C
DC
Desmoulière
A
A
Kisiel
W
W
Rosenbaum
J
J
D000818:Animals; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D002455:Cell Division; D002460:Cell Line; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000378:metabolism; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D015723:Gene Library; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011257:Pregnancy Proteins / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D006023:Glycoproteins; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; C021240:tissue-factor-pathway inhibitor 2; D005167:Factor VII; D013925:Thromboplastin; D020928:Mitogen-Activated Protein Kinases; D005341:Fibrinolysin