Backgroud & Aims Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-inosine RNA editing is a recently described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR (adenosine deaminase that act on RNA) enzymes. Emerging evidence suggests a role for RNA editing and ADARs in cancer, however, the relationship between RNA editing and GC development and progression remains unknown. Methods In this study, we leveraged on the next-generation sequencing transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy. Results Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His to Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL. Conclusions Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous next-generation sequencing analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.
Bibliographical noteFunding Information:
Funding This work was supported by the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Centres of Excellence initiative, NMRC Clinician Scientist-Individual Research Grant New Investigator Grant (CS-IRG NIG, grant number: NMRC/CNIG/1117/2014); NMRC Clinician Scientist-Individual Research Grant (CS-IRG, grant number: NMRC/CIRG/1412/2014); NUS Young Investigator Award (NUS YIA, grant number: NUSYIA_FY14_P22), NUS Start-up Fund (Ref number: NUHSRO/2015/095/SU/01); and core grants from Duke-NUS, GIS, and NMRC/TCR/009-NUHS/2013. The latter was supported through the National Medical Research Council/National Research Foundation Translational and Clinical Research (TCR) Flagship Program. This research is also supported by the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s Tier 3 grants (MOE2014-T3-1-006).
© 2016 AGA Institute
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