Increased E1AF expression in mouse fibrosarcoma promotes metastasis through induction of MT1-MMP expression.
In this study, we investigated the role of E1AF, a member of ets family transcription factor, in the acquisition of metastatic capacity by non-metastatic mouse fibrosarcoma cell clone, QR-32. The QR-32 cell clone grows progressively after co-implantation with gelatin sponge in syngeneic C57BL/6 mice. The cell lines (QRsP) established from arising tumors after the co-implantation exhibited enhanced tumorigenicity and pulmonary metastasis in vivo as compared with parent QR-32 cells. The enhanced pulmonary metastasis of QRsP cells was correlated well with augmented production of matrix metalloproteinase-2 (MMP-2) and increased expression of membrane-type 1-MMP (MT1-MMP). The QRsP cells also acquired higher chemokinetic activities to fibronectin and higher invasive activities through a reconstituted basement membrane. Furthermore we observed the elevated mRNA expression of E1AF in QRsP cells compared to parent QR-32 cells. Therefore, we transfected QR-32 cells with E1AF cDNA. Overexpression of E1AF in the QR-32 cells resulted in the induction of MT1-MMP expression and converting an exogenously added precursor MMP-2 into active form. E1AF transfectants exhibited more motile and invasive activities, and moderately increased pulmonary metastatic activities than parental QR-32 cells in vivo, although their metastatic activities were lower than those of QRsP cells. These findings suggest that the increased expression of E1AF in fibrosarcoma contributes to invasive phenotypes including MT1-MMP expression and enhanced cell migration, but not sufficient for exhibiting highly metastatic activity in vivo.
Habelhah
H
H
Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan.
Okada
F
F
Kobayashi
M
M
Nakai
K
K
Choi
S
S
Hamada
J
J
Moriuchi
T
T
Kaya
M
M
Yoshida
K
K
Fujinaga
K
K
Hosokawa
M
M
D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D005354:Fibrosarcoma; D005780:Gelatin; D018093:Gelatinases / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D014162:Transfection; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; C079853:ETV4 protein, human; C507096:Mmp14 protein, mouse; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D005780:Gelatin; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14