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Original article
A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma
  1. Tim Hon Man Chan1,2,3,
  2. Chi Ho Lin4,
  3. Lihua Qi1,
  4. Jing Fei1,
  5. Yan Li2,3,5,
  6. Kol Jia Yong1,
  7. Ming Liu2,3,
  8. Yangyang Song2,3,
  9. Raymond Kwok Kei Chow2,
  10. Vanessa Hui En Ng1,
  11. Yun-Fei Yuan6,
  12. Daniel G Tenen1,7,
  13. Xin-Yuan Guan2,3,5,
  14. Leilei Chen1
  1. 1Cancer Science Institute of Singapore, National University of Singapore, Singapore
  2. 2Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
  3. 3State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
  4. 4Genome Research Centre, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
  5. 5State Key Laboratory of Oncology in Southern China, Cancer Centre, Sun Yat-sen University Cancer Centre, Guangzhou, China
  6. 6Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Centre, Guangzhou, China
  7. 7Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr L Chen, Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore; csicl{at}nus.edu.sg

Abstract

Objective Hepatocellular carcinoma (HCC) is a heterogeneous tumour displaying a complex variety of genetic and epigenetic changes. In human cancers, aberrant post-transcriptional modifications, such as alternative splicing and RNA editing, may lead to tumour specific transcriptome diversity.

Design By utilising large scale transcriptome sequencing of three paired HCC clinical specimens and their adjacent non-tumour (NT) tissue counterparts at depth, we discovered an average of 20 007 inferred A to I (adenosine to inosine) RNA editing events in transcripts. The roles of the double stranded RNA specific ADAR (Adenosine DeAminase that act on RNA) family members (ADARs) and the altered gene specific editing patterns were investigated in clinical specimens, cell models and mice.

Results HCC displays a severely disrupted A to I RNA editing balance. ADAR1 and ADAR2 manipulate the A to I imbalance of HCC via their differential expression in HCC compared with NT liver tissues. Patients with ADAR1 overexpression and ADAR2 downregulation in tumours demonstrated an increased risk of liver cirrhosis and postoperative recurrence and had poor prognoses. Due to the differentially expressed ADAR1 and ADAR2 in tumours, the altered gene specific editing activities, which was reflected by the hyper-editing of FLNB (filamin B, β) and the hypo-editing of COPA (coatomer protein complex, subunit α), are closely associated with HCC pathogenesis. In vitro and in vivo functional assays prove that ADAR1 functions as an oncogene while ADAR2 has tumour suppressive ability in HCC.

Conclusions These findings highlight the fact that the differentially expressed ADARs in tumours, which are responsible for an A to I editing imbalance, has great prognostic value and diagnostic potential for HCC.

  • Cancer
  • Molecular Carcinogenesis
  • Gene Expression
  • Gene Regulation
  • Molecular Pathology

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

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