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Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma

Abstract

A better understanding of human hepatocellular carcinoma (HCC) pathogenesis at the molecular level will facilitate the discovery of tumor-initiating events. Transcriptome sequencing revealed that adenosine-to-inosine (A→I) RNA editing of AZIN1 (encoding antizyme inhibitor 1) is increased in HCC specimens. A→I editing of AZIN1 transcripts, specifically regulated by ADAR1 (encoding adenosine deaminase acting on RNA-1), results in a serine-to-glycine substitution at residue 367 of AZIN1, located in β-strand 15 (β15) and predicted to cause a conformational change, induced a cytoplasmic-to-nuclear translocation and conferred gain-of-function phenotypes that were manifested by augmented tumor-initiating potential and more aggressive behavior. Compared with wild-type AZIN1 protein, the edited form has a stronger affinity to antizyme, and the resultant higher AZIN1 protein stability promotes cell proliferation through the neutralization of antizyme-mediated degradation of ornithine decarboxylase (ODC) and cyclin D1 (CCND1). Collectively, A→I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.

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Figure 1: AZIN1 overediting is strongly associated with HCC pathogenesis.
Figure 2: ADAR1 directs A→I AZIN1 RNA editing.
Figure 3: AZIN1 RNA editing confers enhanced tumorigenicity.
Figure 4: AZIN1 editing contributes to augmented tumor-initiating potential and enhanced in vivo tumorigenic ability.
Figure 5: RNA editing of AZIN1 changes subcellular localization.
Figure 6: Edited AZIN1 neutralizes antizyme-mediated degradation of target oncoproteins in vitro and in vivo.

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Acknowledgements

We thank and acknowledge the patients for tumor tissue donation to our tissue bank and M. Fullwood (Cancer Science Institute of Singapore, National University of Singapore, Singapore) for providing complementary DNA (cDNA) samples of normal tissues. We thank K. Man and C.M. Lo (Department of Surgery, The University of Hong Kong) for providing healthy human liver tissues. This work was supported by Hong Kong Research Grant Council grants, including the Theme-based Research Scheme Fund (T12-403/11) (X.-Y.G.), Collaborative Research Funds (HKBU5/CRF/10, HKU7/CRG/09 and HKU3/CRF/11R) (X.-Y.G.), the General Research Fund (HKU/766811M) (X.-Y.G.), the China National Basic Research Program (2012CB967001) (X.-Y.G.), the 'Hundred Talents Program' at Sun Yat-Sen University (85000-3171311) (X.-Y.G.), the China National Key Science-Technology Special Project of Infectious Diseases (2008ZX10002-022) (X.-Y.G.) and the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award (D.G.T).

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L.C., Yan Li (Department of Clinical Oncology, The University of Hong Kong, Hong Kong) and X.-Y.G. initiated and designed the study. L.C. wrote the manuscript with input from D.G.T. and X.-Y.G. L.C., Yan Li (Department of Clinical Oncology, The University of Hong Kong, Hong Kong) and C.H.L. designed the experiments and interpreted the results. L.C. and Yan Li (Department of Clinical Oncology, The University of Hong Kong, Hong Kong) performed all experiments with assistance from T.H.M.C., Y.S., M.L., L.Q. and R.K.K.C. Illumina mRNA library preparation was performed by N.Z. and A.H.Y.T. C.H.L. and S.L. performed all bioinformatics analyses of transcriptome sequencing. HCC clinical samples and the relevant clinical information were provided by Y.-F.Y. and extracted by L.C. and Yan Li (State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China). Healthy human liver tissues were provided by K.M. and C.M.L. Human PBMCs were collected by L.F. NPC samples were provided and extracted by D.L.-W.K., K.L.K. and L.C. D.G.T. and X.-Y.G. supervised the project.

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Correspondence to Daniel G Tenen or Xin-Yuan Guan.

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Chen, L., Li, Y., Lin, C. et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med 19, 209–216 (2013). https://doi.org/10.1038/nm.3043

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