Widespread 8-oxoguanine modifications of miRNA seeds differentially regulate redox-dependent cancer development

Oxidative stress contributes to tumourigenesis by altering gene expression. One accompanying modification, 8-oxoguanine (o 8 G) can change RNA–RNA interactions via o 8 G•A base pairing, but its regulatory roles remain elusive. Here, on the basis of o 8 G-induced guanine-to-thymine (o 8 G > T) variations featured in sequencing, we discovered widespread position-specific o 8 Gs in tumour microRNAs, preferentially oxidized towards 5′ end seed regions (positions 2–8) with clustered sequence patterns and clinically associated with patients in lower-grade gliomas and liver hepatocellular carcinoma. We validated that o 8 G at position 4 of miR-124 (4o 8 G-miR-124) and 4o 8 G-let-7 suppress lower-grade gliomas, whereas 3o 8 G-miR-122 and 4o 8 G-let-7 promote malignancy of liver hepatocellular carcinoma by redirecting the target transcriptome to oncogenic regulatory pathways. Stepwise oxidation from tumour-promoting 3o 8 G-miR-122 to tumour-suppressing 2,3o 8 G-miR-122 occurs and its specific modulation in mouse liver effectively attenuates diethylnitrosamine-induced hepatocarcinogenesis. These findings provide resources and insights into epitranscriptional o 8 G regulation of microRNA functions, reprogrammed by redox changes, implicating its control for cancer treatment.