EGF-reduced Wnt5a transcription 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.

• Authors: Yujie Zhang, Jun Du, Jianchao Zheng, Jiaojing Liu, Rui Xu, Tian Shen, Yichao Zhu, Jun Chang, Hong Wang, Zhihong Zhang, Fanqing Meng, Yan Wang, Yongchang Chen, Yong Xu, Luo Gu
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 9 Pg. 7244-61 (Mar 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25779663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ADP-Ribosylation Factor 6
• Proto-Oncogene Proteins
• WNT5A protein, human
• Wnt Proteins
• Wnt-5a Protein
• Epidermal Growth Factor
• Extracellular Signal-Regulated MAP Kinases
• ADP-Ribosylation Factors
• ARF6 protein, human

Topics

• ADP-Ribosylation Factor 6
• ADP-Ribosylation Factors (metabolism)
• Base Sequence
• Cell Differentiation
• Cell Line, Tumor
• Cell Movement
• Epidermal Growth Factor (metabolism)
• Epithelial-Mesenchymal Transition
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Profiling
• Gene Expression Regulation
• Humans
• Molecular Sequence Data
• Neoplasm Metastasis
• Phosphorylation
• Prognosis
• Proto-Oncogene Proteins (metabolism)
• Signal Transduction
• Stomach Neoplasms (metabolism)
• Wnt Proteins (metabolism)
• Wnt-5a Protein