Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogenes.
A human placenta cDNA expression library was screened for genes inducing flat reversion when transfected into a v-K-ras-transformed NIH3T3 cell line, DT. One such gene was found to encode a Kunitz-type serine protease inhibitor, tissue factor pathway inhibitor-2 (TFPI-2). While the TFPI-2 mRNA can be detected in normal human fibroblasts (MRC-5), it is down-regulated in MRC-5 cells expressing an activated H-ras oncogene and in the human fibrosarcoma cell line, HT1080. Restored expression of the TFPI-2 gene in HT1080 cells resulted in the suppression of matrix invasion activity in vitro with concomitant decrease in the relative amount of active matrix metalloproteinase-2 secreted from the cells. When DT cells were cultured in the presence of conditioned medium and extracellular matrix prepared from TFPI-2-transfected HT1080 cells, increased attachment and flat reversion were observed. These results suggest that TFPI-2 may be required for the maintenance of the integrity of extracellular matrix in normal tissues and its down-regulation as a result of oncogene activation may contribute to the malignant phenotypes of tumor cells.
Izumi
H
H
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, 606-8501, Japan.
Takahashi
C
C
Oh
J
J
Noda
M
M
D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D048429:Cell Size; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003001:Cloning, Molecular; D017077:Culture Media, Conditioned; D015536:Down-Regulation; D004789:Enzyme Activation; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D011257:Pregnancy Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D017077:Culture Media, Conditioned; D006023:Glycoproteins; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C021240:tissue-factor-pathway inhibitor 2; D020778:Matrix Metalloproteinase 2; D018631:ras Proteins