title: Integrated microRNA network analyses identify a poor-prognosis subtype of gastric cancer characterized by the miR-200 family.
abstract: OBJECTIVE
  Our aim was to investigate whether microRNAs can predict the clinical outcome of patients with gastric cancer. We used integrated analysis of microRNA and mRNA expression profiles to identify gastric cancer microRNA subtypes and their underlying regulatory scenarios.
  
  
  METHODS
  MicroRNA-based gastric cancer subtypes were identified by consensus clustering analysis of microRNA profiles of 90 gastric cancer tissues. Activated pathways in the subtypes were identified by gene expression profiles. Further integrated analysis was conducted to model a microRNA regulatory network for each subtype. RNA and protein expression were analyzed by RT-PCR and tissue microarray, respectively, in a cohort of 385 gastric cancer cases (including the 90 cases for profiling) to validate the key microRNAs and targets in the network. Both in vitro and in vivo experiments were carried out to further validate the findings.
  
  
  RESULTS
  MicroRNA profiles of 90 gastric cancer cases identified two microRNA subtypes significantly associated with survival. The poor-prognosis gastric cancer microRNA subtype was characterized by overexpression of epithelial-to-mesenchymal transition (EMT) markers. This gastric cancer "mesenchymal subtype" was further validated in a patient cohort comprising 385 cases. Integrated analysis identified a key microRNA regulatory network likely driving the gastric cancer mesenchymal subtype. Three of the microRNAs (miR-200c, miR-200b, and miR-125b) targeting the most genes in the network were significantly associated with survival. Functional experiments demonstrated that miR-200b suppressed ZEB1, augmented E-cadherin, inhibited cell migration, and suppressed tumor growth in a mouse model.
  
  
  CONCLUSIONS
  We have uncovered a key microRNA regulatory network that defines the mesenchymal gastric cancer subtype significantly associated with poor overall survival in gastric cancer.
authors.affiliation: Authors' Affiliations: Departments of Epidemiology and Biostatistics, Immunology, and Gastric Cancer, TMUCIH-J&J Joint Laboratory, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital; Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, PR China; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Janssen Research and Development, a Division of Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Fengju
authors.initials: F
authors.lastname: Song
authors.forename: Da
authors.initials: D
authors.lastname: Yang
authors.forename: Ben
authors.initials: B
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Jinpu
authors.initials: J
authors.lastname: Yu
authors.forename: Yanrui
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ruifang
authors.initials: R
authors.lastname: Niu
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.forename: Hans
authors.initials: H
authors.lastname: Winkler
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xishan
authors.initials: X
authors.lastname: Hao
authors.forename: Kexin
authors.initials: K
authors.lastname: Chen
mesh_terms: D000368:Aged; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010641:Phenotype; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1