Widespread o8G oxidation of miRNAs modulates tumor development. homo sapiens, mus musculus & rattus norvegicus

Reactive oxygen species control tumor development, featuring oxidative modification. 8-oxoguanine (o8G) of microRNA (miRNA) could redirect target gene silencing by inducing o8G:A base pairing, but its reprogramming potential in cancer remains elusive. Here, by analyzing and sequencing o8G-miRNAs with guanine-to-thymine (G>T) positions, we find that o8G prevails in seed regions (positions 2-8) of miRNAs in cancer patients and a rat model of liver hepatocellular carcinoma (LIHC). Such o8G-miRNAs include miR-124, let-7 and miR-122, distinctly functioning in tumor malignancy; o8G at position 4 of miR-124 (4o8G-miR-124) and 4o8G-let-7 suppress glioma cells, but 3o8G-miR-122 and 4o8G-let-7 promote LIHC. Stepwise oxidation of miR-122 is elucidated in LIHC, accumulating from 2o8G to 3o8G and becoming tumor-suppressive (2,3o8G-miR-122). Such functional transition was caused by change of global miRNA targets via o8G:A base pairing and further validated using in vivo mouse models. Our results provide o8G-miRNA sequences to understand redox-mediated epitranscriptional regulation in tumorigenesis.