Enhanced Expression of Integrin αvβ3 Induced by TGF-β Is Required for the Enhancing Effect of Fibroblast Growth Factor 1 (FGF1) in TGF-β-Induced Epithelial-Mesenchymal Transition (EMT) in Mammary Epithelial Cells.
Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis, and is regulated by growth factors such as transforming growth factor β (TGF-β) and fibroblast growth factors (FGF) secreted from the stromal and tumor cells. However, the role of growth factors in EMT has not been fully established. Several integrins are upregulated by TGF-β1 during EMT. Integrins are involved in growth factor signaling through integrin-growth factor receptor crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and the interaction was required for FGF1 functions such as cell proliferation and migration. We studied the role of αvβ3 induced by TGF-β on TGF-β-induced EMT. Here, we describe that FGF1 augmented EMT induced by TGF-β1 in MCF10A and MCF12A mammary epithelial cells. TGF-β1 markedly amplified integrin αvβ3 and FGFR1 (but not FGFR2). We studied if the enhancing effect of FGF1 on TGF-β1-induced EMT requires enhanced levels of both integrin αvβ3 expression and FGFR1. Knockdown of β3 suppressed the enhancement by FGF1 of TGF-β1-induced EMT in MCF10A cells. Antagonists to FGFR suppressed the enhancing effect of FGF1 on EMT. Integrin-binding defective FGF1 mutant did not augment TGF-β1-induced EMT in MCF10A cells. These findings suggest that enhanced integrin αvβ3 expression in addition to enhanced FGFR1 expression is critical for FGF1 to augment TGF-β1-induced EMT in mammary epithelial cells.
Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, 1-7 Yamada-oka, Suita-shi, Osaka, 565-0871, Japan.
Seiji
S
Mori
Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, 1-7 Yamada-oka, Suita-shi, Osaka, 565-0871, Japan.
Moe
M
Kodaira
Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, 1-7 Yamada-oka, Suita-shi, Osaka, 565-0871, Japan.
Ayano
A
Ito
Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, 1-7 Yamada-oka, Suita-shi, Osaka, 565-0871, Japan.
Mika
M
Okazaki
Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, 1-7 Yamada-oka, Suita-shi, Osaka, 565-0871, Japan.
Naomasa
N
Kawaguchi
Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, 1-7 Yamada-oka, Suita-shi, Osaka, 565-0871, Japan.
Yoshinosuke
Y
Hamada
Departments of Dermatology, Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, California, 95817, United States of America; Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 520 Wu-Hsing Street, Taipei, 11031, Taiwan, R.O.C.
Yoshikazu
Y
Takada
Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, 1-7 Yamada-oka, Suita-shi, Osaka, 565-0871, Japan.
Nariaki
N
Matsuura
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D039302:Integrin alphaVbeta3; D016212:Transforming Growth Factor beta; D016220:Fibroblast Growth Factor 1; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1