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MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1
  1. Tae-Su Han1,2,
  2. Keun Hur3,4,
  3. Guorong Xu5,
  4. Boram Choi1,
  5. Yoshinaga Okugawa3,6,
  6. Yuji Toiyama6,
  7. Hiroko Oshima2,
  8. Masanobu Oshima2,
  9. Hyuk-Joon Lee1,7,
  10. V Narry Kim8,
  11. Aaron N Chang5,
  12. Ajay Goel3,
  13. Han-Kwang Yang1,7
  1. 1Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
  2. 2Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
  3. 3Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, USA
  4. 4Biomedical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
  5. 5Baylor Institute for Immunology Research and Baylor Research Institute, Baylor University Medical Center, Dallas, USA
  6. 6Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
  7. 7Departments of Surgery, Seoul National University College of Medicine, Seoul, Korea
  8. 8Department of Biological Sciences, Seoul National University, Seoul, Korea
  1. Correspondence to Dr Ajay Goel, Gastrointestinal Cancer Research Laboratory, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA; ajay.goel{at} or Dr Han-Kwang Yang, Cancer Research Institute, Department of Surgery, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongno-gu, Seoul 110-744 Korea; hkyang{at}


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.

Design 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.

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