The Role Of Wnt5a In EGF Signaling Pathway In The Induction Of Epithelial-mesenchymal Transition In Gastric Cancer Cells

Wnt5a,a ligand for activating the non-canonical Wnt signaling pathway,is commonly associated with EMT(epithelial-to-mesenchymal transition)in cancer cell metastasis.Here,we show that downregulation of Wnt5 a mRNA and protein by EGF(epidermal growth factor)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 Wnt5 a expression.EGF increased Arf6 and ERK(extracellular regulated protein kinases)activity,while blockade of Arf6 activation repressed ERK activity,up-regulated Wnt5 a expression and repressed EMT in response to EGF.We also demonstrate that EGF inactivated Wnt5 a transcription by direct recruitment of ERK to the Wnt5 a promoter.On the other hand,inhibition of ERK phosphorylation resulted in decreased movement of ERK from the cytoplasm to the nucleus,following rescued Wnt5 a 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 Wnt5 a transcription.Analysis of gastric cancer specimens revealed an inverse correlation between P-ERK and Wnt5 a protein levels and an association between Wnt5 a expression and better prognosis.These findings indicate that Wnt5 a is a potential suppressor of EMT and identify a novel Arf6/ERK signaling pathway for EGF-regulated Wnt5 a expression at transcriptional level of gastric cancer cells.