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 center dot 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 4o8G-let-7 suppress lower-grade gliomas, whereas 3o8G-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.

Automated summary

Oxidative stress contributes to tumourigenesis by altering gene expression. One modification, 8-oxoguanine, can change RNA-RNA interactions, but its regulatory roles are not well understood. Sequencing analysis revealed widespread position-specific 8-oxoguanine in tumour microRNAs, which are associated with lower-grade gliomas and liver hepatocellular carcinoma. Specific 8-oxoguanine modifications were found to suppress or promote the malignancy of cancer, suggesting its potential importance in cancer treatment.