Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma
Menée à partir d'échantillons tumoraux prélevés sur plusieurs cohortes de patients chinois atteints d'un carcinome hépatocellulaire, sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel le remplacement d'un nucléoside par un autre dans les transcrits du gène AZIN1 favorise le développement de la maladie
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 (Aright arrowI) RNA editing of AZIN1 (encoding antizyme inhibitor 1) is increased in HCC specimens. Aright arrowI 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, Aright arrowI RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.