EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells
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Yujie Zhang1,2,3, Jun Du1,3, Jianchao Zheng3, Jiaojing Liu2, Rui Xu4, Tian Shen3, Yichao Zhu3, Jun Chang2, Hong Wang2, Zhihong Zhang5, Fanqing Meng6, Yan Wang7, Yongchang Chen8, Yong Xu9, Luo Gu1,2,3
1Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China
2Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
3Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
4Department of Biotechnology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
5Department of Pathophysiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
6Department of Pathophysiology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China
7Department of Pathophysiology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China
8Department of Physiology, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
9Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
Luo Gu, e-mail: [email protected]
Keywords: EGF, Arf6, ERK, Wnt5a, EMT
Received: August 15, 2014 Accepted: January 11, 2015 Published: March 12, 2015
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.
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