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.

Seiji Mori,Moe Kodaira,Yoshinosuke Hamada,Yoshikazu Takada,Naomasa Kawaguchi,Mika Okazaki,Ayano Ito,Nariaki Matsuura,Irina U Agoulnik

doi:10.1371/journal.pone.0137486

Abstract

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.

Highlights

Dynamic cross-regulation of growth factors is a hallmark of epithelial-mesenchymal transition (EMT) [1,2,3]
We studied the effect of FGF1 on TGF-β1-induced EMT in MCF10A human mammary epithelial cells
In contrast to this model, we reported that FGF1 directly binds to integrin αvβ3 and induces the FGFR1-FGF1-integrin αvβ3 ternary complex, and the interaction increases fibroblast and endothelial cell growth and motility [20, 22]

Summary

Introduction

Dynamic cross-regulation of growth factors is a hallmark of epithelial-mesenchymal transition (EMT) [1,2,3]. Fibroblast growth factors (FGFs) control multiple biological processes such as proliferation, survival, migration and differentiation of a variety of cell types [4, 5]. FGF signaling plays a role in EMT and morphogenesis of mesoderm in mice at gastrulation by controlling Snail that inhibits E-cadherin expression [6]. FGF signaling is necessary to control a specification of mesodermal and endodermal fates through some of the genes involved in the EMT during development [7]. Deregulation of FGF signaling in different types of cancer has been reported. Aberrant FGF signaling promotes tumor development by directly regulating cancer cell proliferation, survival, and by promoting tumor angiogenesis [9]

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Conclusion