Fibroblast Growth Factor 2 Induces E-Cadherin Down-Regulation via PI3K/Akt/mTOR and MAPK/ERK Signaling in Ovarian Cancer Cells

Abstract

Fibroblast growth factor 2 (FGF2) is produced by ovarian cancer cells and it has been suggested to play an important role in tumor progression. In this study, we report that FGF2 treatment down-regulated E-cadherin by up-regulating its transcriptional repressors, Slug and ZEB1, in human ovarian cancer cells. The pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR), and MEK suggests that both PI3K/Akt/mTOR and MAPK/ERK signaling are required for FGF2-induced E-cadherin down-regulation. Moreover, FGF2 up-regulated Slug and ZEB1 expression via the PI3K/Akt/mTOR and MAPK/ERK signaling pathways, respectively. Finally, FGF2-induced cell invasion was abolished by the inhibition of the PI3K/Akt/mTOR and MAPK/ERK pathways, and the forced expression of E-cadherin diminished the intrinsic invasiveness of ovarian cancer cells as well as the FGF2-induced cell invasion. This study demonstrates a novel mechanism in which FGF2 down-regulates E-cadherin expression through the activation of PI3K/Akt/mTOR and MAPK/ERK signaling, and the up-regulation of Slug and ZEB1 in human ovarian cancer cells.

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

“…This strongly suggests that corneal endothelial cells behave differently ex vivo versus in vitro. Moreover, suppression of E-cadherin expression by FGF2 treatment in corneal endothelial cells also supports conversion to a mesenchymal phenotype and is consistent with previous reports showing similar results in ovarian cancer cells (34,36).…”

“…Another key inducer of mesenchymal transition is FGF2 (34)(35)(36), and SNAI1 has been reported to be a downstream target of FGF2, during chondrogenesis and in certain forms of achondroplasia (37). We previously reported that FGF2 signals through PI 3-kinase to induce mesenchymal transition in rabbit and human CEC.…”

Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling

“…Ras/ERK1/2 activation seems to be a necessary step in the induction of EMT (22,42,48). Also, it is reported that ERK1/2 and/or Akt is an important mechanism in EMT induced by various mediators such as TGF-␤, EGF, and FGF-2 (27,48). Our study demonstrated that kindlin-2 induced tubular EMT through Ras/ERK1/2 and Ras/Akt pathways.…”

Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells

“…EMT is a reversible process, whereby the epithelial cells lose their junctions and polarity, reorganize their cytoskeleton, gain ability of motility, transit into mesenchymal cells and develop an invasive phenotype (30). The functional loss of E-cadherin is the typical characteristic of EMT and this contributes to the destabilization of adheren junctions, as well as tumor invasion and metastasis (20,30,47,48). Therefore, SFN is capable of suppressing the process of EMT by inducing E-cadherin.…”