A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma

Chan, Tim; Lin, Chi Ho; Liu, Qi; Jing, Fei; Li, Yan; Yong, Kol Jia; Liu, Ming; Song, Yangyang; Chow, Raymond Kwok Kei; Ng, Vanessa Hui En; Yuan, Yunfei; Tenen, Daniel G.; Guan, Xin Yuan; Chen, Leilei

doi:10.1136/gutjnl-2012-304037

Cited by 197 publications

(222 citation statements)

References 33 publications

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“…Thus, levels of editing in mature mRNAs may also be regulated by differential splicing. Moreover, Flnb editing has been shown to be altered in esophageal and liver carcinomas due to the increased activity of ADAR1 indicating that this enzyme may also target Flnb , at least under specific conditions [38,39]. Clearly, further investigations concerning the modulation of Flnb RNA editing will be required.…”

Section: Discussionmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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Adenosine to inosine RNA editing in protein-coding messenger RNAs (mRNAs) potentially leads to changes in the amino acid composition of the encoded proteins. The mRNAs encoding the ubiquitously expressed actin-crosslinking proteins Filamin A and Filamin B undergo RNA editing leading to a highly conserved glutamine to arginine exchange at the identical position in either protein. Here, by targeted amplicon sequencing we analysed the RNA editing of Filamin B across several mouse tissues during post-natal development. We find highest filamin B editing levels in skeletal muscles, cartilage and bones, tissues where Filamin B function seems most important. Through the analysis of Filamin B editing in mice deficient in either ADAR1 or 2, we identified ADAR2 as the enzyme responsible for Filamin B RNA editing. We show that in neuronal tissues Filamin B editing drops in spliced transcripts indicating regulated maturation of edited transcripts. We show further that the variability of Filamin B editing across several organs correlates with its mRNA expression.

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Section: Discussionmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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“…Therefore, ADAR1 and ADAR2, both, would edit the AhR 3Ј-UTR. Although a previous study (11) reported that ADAR2 is functionally expressed in normal human livers, hepatic ADAR2 protein was not detected in this study even when an antibody from another vendor was used (data not shown). Because of the lower expression level of ADAR2 compared with ADAR1, the role of ADAR2 in RNA editing in human livers may be only minor.…”

Section: Discussionmentioning

confidence: 40%

“…6B). To investigate whether the small interindividual variability in RNA editing levels in the human livers was specific for AhR, we examined the RNA editing levels in filamin B, ␤, which has been reported to be edited by ADAR1 (11). The RNA editing levels were correlated with ADAR1 p110 expression, and the interindividual variability was relatively large compared with that of AhR (Fig.…”

Section: Rna Editing Of the Ahr Transcriptmentioning

confidence: 99%

“…Recently, it has been reported that ADAR1 and ADAR2 mRNA expression were increased and decreased, respectively, in human hepatocellular carcinoma specimens compared with non-tumor liver specimens (11). In this study we sought to examine the extent of the interindividual variability in ADAR expression in normal human livers and its impact on the expression or function of drug metabolizing-related genes.…”

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confidence: 99%

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RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence

Nakano

Fukami

Gotoh

et al. 2016

Journal of Biological Chemistry

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Adenosine to inosine (A-to-I) RNA editing is the most frequent type of post-transcriptional nucleotide conversion in humans, and it is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. In this study we investigated the effect of RNA editing on human aryl hydrocarbon receptor (AhR) expression because the AhR transcript potentially forms double-stranded structures, which are targets of ADAR enzymes. In human hepatocellular carcinoma-derived Huh-7 cells, the ADAR1 knockdown reduced the RNA editing levels in the 3-untranslated region (3-UTR) of the AhR transcript and increased the AhR protein levels. The ADAR1 knockdown enhanced the ligand-mediated induction of CYP1A1, a gene downstream of AhR. We investigated the possibility that A-to-I RNA editing creates miRNA targeting sites in the AhR mRNA and found that the miR-378-dependent down-regulation of AhR was abolished by ADAR1 knockdown. These results indicated that the ADAR1-mediated down-regulation of AhR could be attributed to the creation of a miR-378 recognition site in the AhR 3-UTR. The interindividual differences in the RNA editing levels within the AhR 3-UTR in a panel of 32 human liver samples were relatively small, whereas the differences in ADAR1 expression were large (220-fold). In the human liver samples a significant inverse association was observed between the miR-378 and AhR protein levels, suggesting that the RNA-editingdependent down-regulation of AhR by miR-378 contributes to the variability in the constitutive hepatic expression of AhR. In conclusion, this study uncovered for the first time that A-to-I RNA editing modulates the potency of xenobiotic metabolism in the human liver.

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“…Furthermore, it was recently reported that ADAR1 is involved in the development of liver carcinoma. 74 It will be interesting to investigate whether there is a connection between its anti-inflammatory effects and its oncogenic functions.…”

Section: Adar1 In Liver Homeostasismentioning

confidence: 99%

ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes

Wang

Singh

et al. 2015

The American Journal of Pathology

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Adenosine deaminase acting on RNA 1 (ADAR1) is an essential protein for embryonic liver development. ADAR1 loss is embryonically lethal because of severe liver damage. Although ADAR1 is required in adult livers to prevent liver cell death, as demonstrated by liver-specific conditional knockout (Alb-ADAR1 KO ) mice, the mechanism remains elusive. We systematically analyzed Alb-ADAR1 KO mice for liver damage. Differentiation genes and inflammatory pathways were examined in hepatic tissues from Alb-ADAR1 KO and littermate controls. Inducible ADAR1 KO mice were used to validate regulatory effects of ADAR1 on inflammatory cytokines. We found that Alb-ADAR1 KO mice showed dramatic growth retardation and high mortality because of severe structural and functional damage to the liver, which showed overwhelming inflammation, cell death, fibrosis, fatty change, and compensatory regeneration. Simultaneously, Alb-ADAR1 KO showed altered expression of key differentiation genes and significantly higher levels of hepatic inflammatory cytokines, especially type I interferons, which was also verified by inducible ADAR1 knockdown in primary hepatocyte cultures. We conclude that ADAR1 is an essential molecule for maintaining adult liver homeostasis and, in turn, morphological and functional integrity. It inhibits the production of type I interferons and other inflammatory cytokines. Our findings may provide novel insight in the pathogenesis of liver diseases caused by excessive inflammatory responses, including autoimmune hepatitis. (Am J Pathol 2015, 185: 3224e3237; http://dx

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A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma

Cited by 197 publications

References 33 publications

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence

ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes

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