title: MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1.
abstract: OBJECTIVE
  Gastric cancer (GC) remains difficult to cure due to heterogeneity in a clinical challenge and the molecular mechanisms underlying this disease are complex and not completely understood. Accumulating evidence suggests that microRNAs (miRNAs) play an important role in GC, but the role of specific miRNAs involved in this disease remains elusive. We performed next generation sequencing (NGS)-based whole-transcriptome profiling to discover GC-specific miRNAs, followed by functional validation of results.
  
  
  METHODS
  NGS-based miRNA profiles were generated in matched pairs of GCs and adjacent normal mucosa (NM). Quantitative RT-PCR validation of miR-29c expression was performed in 274 gastric tissues, which included two cohorts of matched GC and NM specimens. Functional validation of miR-29c and its gene targets was undertaken in cell lines, as well as K19-C2mE and K19-Wnt1/C2mE transgenic mice.
  
  
  RESULTS
  NGS analysis revealed four GC-specific miRNAs. Among these, miR-29c expression was significantly decreased in GC versus NM tissues (p<0.001). Ectopic expression of miR-29c mimics in GC cell lines resulted in reduced proliferation, adhesion, invasion and migration. High miR-29c expression suppressed xenograft tumour growth in nude mice. Direct interaction between miR-29c and its newly discovered target, ITGB1, was identified in cell lines and transgenic mice. MiR-29c expression demonstrated a stepwise decrease in wild type hyperplasia-dysplasia cascade in transgenic mice models of GC.
  
  
  CONCLUSIONS
  MiR-29c acts as a tumour suppressor in GC by directly targeting ITGB1. Loss of miR-29c expression is an early event in the initiation of gastric carcinogenesis and may serve as a diagnostic and therapeutic biomarker for patients with GC.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Tae-Su
authors.initials: TS
authors.lastname: Han
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, USA Biomedical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Keun
authors.identifier: http://orcid.org/0000-0002-6944-2718
authors.initials: K
authors.lastname: Hur
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Baylor University Medical Center, Dallas, USA.
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Boram
authors.initials: B
authors.lastname: Choi
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, USA Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Okugawa
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oshima
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Departments of Surgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyuk-Joon
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: V Narry
authors.initials: VN
authors.lastname: Kim
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Baylor University Medical Center, Dallas, USA.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Chang
authors.affiliation: Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Departments of Surgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Han-Kwang
authors.initials: HK
authors.lastname: Yang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics*; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D012334:RNA, Neoplasm / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: D019012:Integrin beta1; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm