title: GEP100 regulates epidermal growth factor-induced MDA-MB-231 breast cancer cell invasion through the activation of Arf6/ERK/uPAR signaling pathway.
abstract: GEP100, a guanine nucleotide exchanging factor (GEF) for Arf6, plays a pivotal role in promoting breast cancer cell invasion both in vitro and in vivo. However, the precise mechanism for GEP100-mediated cell invasion is still poorly understood. In this study, we found that down-regulation of endogenous GEP100 in MDA-MB-231 cells significantly inhibited EGF-induced cell invasion, which was rescued by over-expression of ectopic GEP100. EGF increased Arf6 activity, ERK phosphorylation, and uPAR expression in a time dependent manner. Additionally, blocking Arf6 with Arf6 siRNA largely abolished EGF-induced cell invasion. GEP100 siRNA or Arf6 siRNA suppressed EGF-induced ERK activity and uPAR expression. Furthermore, blocking ERK signaling with U0126, a specific inhibitor for MEK, markedly inhibited EGF-induced uPAR expression and consequently cell invasion. Inhibition of uPAR expression by uPAR siRNA also significantly abolished EGF-induced cell invasion. Taken together, this study illustrates that GEP100 regulates an Arf6/ERK/uPAR signaling cascade in EGF-induced breast cancer cell invasion. These findings could provide a rationale for designing new therapies based on inhibition of breast cancer metastasis.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Jiaojing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China; Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: Medicine Technique School, Taizhou Polytechnic College, Taizhou, Jiangsu 225300, PR China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Li
authors.affiliation: Medicine Technique School, Taizhou Polytechnic College, Taizhou, Jiangsu 225300, PR China.
authors.forename: Wanqiu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Medical Sciences and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China; Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China. Electronic address: zhuyichao@njmu.edu.cn.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China; Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China. Electronic address: lgu@njmu.edu.cn.
authors.forename: Luo
authors.initials: L
authors.lastname: Gu
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism* / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000494:pharmacology; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000089982:ADP-Ribosylation Factor 6; D020662:Guanine Nucleotide Exchange Factors; C504483:IQSEC1 protein, human; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human
keywords: Arf6; EGF; ERK; GEP100; Invasion; uPAR