EGF-reducedWnt5atranscription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells

Abstract

Wnt5a, a ligand for activating the non-canonical Wnt signaling pathway, is commonly associated with Epithelial-to-mesenchymal transition (EMT) in cancer cell metastasis. Here, we show that downregulation of Wnt5a mRNA and protein by EGF is necessary for EGF-induced EMT in gastric cancer SGC-7901 cells. To further explore the mechanisms, we investigated the effect of EGF signaling on Wnt5a expression. EGF increased Arf6 and ERK activity, while blockade of Arf6 activation repressed ERK activity, up-regulated Wnt5a expression and repressed EMT in response to EGF. We also demonstrate that EGF inactivated Wnt5a transcription by direct recruitment of ERK to the Wnt5a promoter. On the other hand, inhibition of ERK phosphorylation resulted in decreased movement of ERK from the cytoplasm to the nucleus, following rescued Wnt5a mRNA and protein expression and favored an epithelial phenotype of SGC-7901 cells. In addition, we notice that kinase-dead, nuclear-localised ERK has inhibitory effect on Wnt5a transcription. Analysis of gastric cancer specimens revealed an inverse correlation between P-ERK and Wnt5a protein levels and an association between Wnt5a expression and better prognosis. These findings indicate that Wnt5a is a potential suppressor of EMT and identify a novel Arf6/ERK signaling pathway for EGF-regulated Wnt5a expression at transcriptional level of gastric cancer cells.

Src promotes EGF‐induced epithelial‐to‐mesenchymal transition and migration in gastric cancer cells by upregulating ZEB1 and ZEB2 through AKT

“…Kim et al (2008) reported that EGFR overexpression occurred in 27.4% of gastric cancers and was associated with poor prognosis. Until now, EGF/EGFR signaling pathway has been reported to trigger EMT and migration in a variety of cancer cells, leading to cancer invasion and metastasis (Ha et al, 2013;Zhang et al, 2014), but seldom in gastric cancer cells Chen et al, 2014;Zhang et al, 2015). In the present study, we show that EGF stimulates EMT in gastric cancer cells and promotes their migratory capacities.…”

“…As a receptor tyrosine kinase, EGFR is activated after its binding with EGF, and then the downstream intracellular signaling pathways, such as protein kinase B (AKT), extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) are activated, which lead to the changes of proteins of intercellular junction and cytoskeleton, thus inducing EMT (Avraham and Yarden, 2011). However, EGF-stimulated EMT and migration have been rarely reported in gastric cancer cells Chen et al, 2014;Zhang et al, 2015). However, EGF-stimulated EMT and migration have been rarely reported in gastric cancer cells Chen et al, 2014;Zhang et al, 2015).…”

“…Activation of EGFR has been shown to protect both gastric epithelial cells and gastric cancer cells from apoptosis (Xu et al, 2012;Chaturvedi et al, 2014). However, EGF-stimulated EMT and migration have been rarely reported in gastric cancer cells Chen et al, 2014;Zhang et al, 2015).…”

mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

“…Immunohistochemical staining results were taken by using Axioskop 2 plus microscope (Carl Zeiss). FLCN and HIF2α immunostaining was scored by immune reactive score (IRS) as described previously 20 .…”

Wnt5a Signaling in Gastric Cancer

“…However, limited evidence also suggests the opposite role for Wnt5a. Zhang et al (2015) reported that the downregulation of Wnt5a is required for EGFinduced EMT in the GC cell line SGC-7901. In this report, the knockdown of Wnt5a increased cell migration, while the overexpression of Wnt5a impaired EGF-induced N-Cadherin and Vimentin expression.…”