Tae-Su Han1, Keun Hur2, Guorong Xu3, Boram Choi4, Yoshinaga Okugawa5, Yuji Toiyama6, Hiroko Oshima7, Masanobu Oshima7, Hyuk-Joon Lee8, V Narry Kim9, Aaron N Chang3, Ajay Goel10, Han-Kwang Yang8. 1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 2. 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. 3. Baylor Institute for Immunology Research and Baylor Research Institute, Baylor University Medical Center, Dallas, USA. 4. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. 5. 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. 6. Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan. 7. Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 8. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Departments of Surgery, Seoul National University College of Medicine, Seoul, Korea. 9. Department of Biological Sciences, Seoul National University, Seoul, Korea. 10. Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, USA.
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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Yon Hui Kim; Han Liang; Xiuping Liu; Ju-Seog Lee; Jae Yong Cho; Jae-Ho Cheong; Hoguen Kim; Min Li; Thomas J Downey; Matthew D Dyer; Yongming Sun; Jingtao Sun; Ellen M Beasley; Hyun Cheol Chung; Sung Hoon Noh; John N Weinstein; Chang-Gong Liu; Garth Powis Journal: Cancer Res Date: 2012-03-20 Impact factor: 12.701