Oxidative stress contributes to tumourigenesis by altering gene expression. One accompanying modification, 8-oxoguanine (o8G) can change RNA–RNA interactions via o8G•A base pairing, but its regulatory roles remain elusive. Here, on the basis of o8G-induced guanine-to-thymine (o8G > T) variations featured in sequencing, we discovered widespread position-specific o8Gs 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 o8G at position 4 of miR-124 (4o8G-miR-124) and 4o8G-let-7 suppress lower-grade gliomas, whereas 3o8G-miR-122 and 4o8G-let-7 promote malignancy of liver hepatocellular carcinoma by redirecting the target transcriptome to oncogenic regulatory pathways. Stepwise oxidation from tumour-promoting 3o8G-miR-122 to tumour-suppressing 2,3o8G-miR-122 occurs and its specific modulation in mouse liver effectively attenuates diethylnitrosamine-induced hepatocarcinogenesis. These findings provide resources and insights into epitranscriptional o8G regulation of microRNA functions, reprogrammed by redox changes, implicating its control for cancer treatment.
Bibliographical noteFunding Information:
We thank all members of the Chi laboratory for their help and discussions. We are especially grateful to the late S.-D. Yoo and the Y.S. Lee for motivating us to strive to understand liver cancer. We thank J.-W. Nam for his help in initiating the TCGA data analysis, S.-H. Koo for providing the albumin promoter-containing vector, M.-S. Lee for providing SK-HEP-1, J. Hwang for help with arranging clinical samples, J. H. Kim for his help in preliminary studies on glioblastoma, Y. Koh for help in analysing RNA-seq data, and Y. Jeong, D.-N. Lee, Y. Kang and K.-H. Lee for their initial assistance in preliminary studies. This work was supported by the Samsung Research Funding & Incubation Center of Samsung Electronics under project number SRFC-MA1801-10, grants from the NRF funded by the Ministry of Science, ICT & Future Planning (NRF-2023R1A2C3005802, to S.W.C.; NRF-2021R1I1A1A01045508, to S.E.), Korea University grants, the KU-KIST Graduate School of Converging Science and Technology Program, and Korea Institute of Science and Technology (KIST) Institutional Program (2V09840). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
ASJC Scopus subject areas
- Cell Biology