title: Astrocyte elevated gene-1(AEG-1) induces epithelial-mesenchymal transition in lung cancer through activating Wnt/β-catenin signaling.
abstract: BACKGROUND
  Non-small cell lung cancer (NSCLC) is a highly metastatic cancer with limited therapeutic options, so development of novel therapies that target NSCLC is needed. During the early stage of metastasis, the cancer cells undergo an epithelial-mesenchymal transition (EMT), a phase in which Wnt/β-catenin signaling is known to be involved. Simultaneously, AEG-1 has been demonstrated to activate Wnt-mediated signaling in some malignant tumors.
  
  
  METHODS
  Human NSCLC cell lines and xenograft of NSCLC cells in nude mice were used to investigate the effects of AEG-1 on EMT. EMT or Wnt/β-catenin pathway-related proteins were characterized by western blot, immunofluorescence and immunohistochemistry.
  
  
  RESULTS
  In the present study, we demonstrated that astrocyte elevated gene-1(AEG-1) ectopic overexpression promoted EMT, which resulted from the down-regulation of E-cadherin and up-regulation of Vimentin in lung cancer cell lines and clinical lung cancer specimens. Using an orthotopic xenograft-mouse model, we also observed that AEG-1 overexpression in human carcinoma cells led to the development of multiple lymph node metastases and elevated mesenchymal markers such as Vimentin, which is a characteristic of cells in EMT. Furthermore, AEG-1 functioned as a critical protein in the regulation of EMT by directly targeting multiple positive regulators of the Wnt/β-catenin signaling cascade, including GSK-3β and CKIδ. Notably, overexpression of AEG-1 in metastatic cancer tissues was closely associated with poor survival of NSCLC patients.
  
  
  CONCLUSIONS
  These results reveal the critical role of AEG-1 in EMT and suggest that AEG-1 may be a prognostic biomarker and its targeted inhibition may be utilized as a novel therapy for NSCLC.
authors.affiliation: Department of Gastrointestinal Surgery, Guangzhou, 510080, Province Guangdong, Peoples' Republic of China. heweiling@mail.sysu.edu.cn.
authors.forename: Weiling
authors.initials: W
authors.lastname: He
authors.affiliation: Gynecology, and the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, Peoples' Republic of China. heshanyang@mail.sysu.edu.cn.
authors.forename: Shanyang
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, Guangdong, 510080, Peoples' Republic of China. wangzuo@mail.sysu.edu.cn.
authors.forename: Zuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Gynecology, and the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, Peoples' Republic of China. shenhongwei@mail.sysu.edu.cn.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Oncology, Sun Yat-sen University CancerCenter, Guangzhou, 510060, Province Guangdong, Peoples' Republic of China. wff2007@gmail.com.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Fang
authors.affiliation: College of Engineering, University of Texas, El Paso 500 West University Avenue, El Paso, TX, 79968, USA. yzhang3@miners.utep.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Engineering, University of Texas, El Paso 500 West University Avenue, El Paso, TX, 79968, USA. wqian@utep.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 570 Westwood Plaza, Los Angeles, CA, 90095-1770, USA. mwlin7@gmail.com.
authors.forename: Millicent
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 570 Westwood Plaza, Los Angeles, CA, 90095-1770, USA. dennisyuan@ucla.edu.
authors.forename: Jinglun
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Anatomy, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, 510515, Peoples' Republic of China. wangjinyang@126.com.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anatomy, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, 510515, Peoples' Republic of China. 13822232749@139.com.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, Guangdong, 510080, Peoples' Republic of China. wangliantang@mail.sysu.edu.cn.
authors.forename: Liantang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, Guangdong, 510080, Peoples' Republic of China. kezunfu@126.com.
authors.forename: Zunfu
authors.initials: Z
authors.lastname: Ke
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D016601:RNA-Binding Proteins; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3