title: 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.affiliation: Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China.|Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.|Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China.|Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Jianchao
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Jiaojing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biotechnology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors.forename: Fanqing
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Pathophysiology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China.|Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.|Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Luo
authors.initials: L
authors.lastname: Gu
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D001483:Base Sequence; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D000089982:ADP-Ribosylation Factor 6; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human
keywords: Arf6; EGF; EMT; ERK; Wnt5a