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

Sep 11, 2023Nature cell biology

Oxidative changes in microRNA seeds influence cancer growth linked to cell redox state

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Abstract

Widespread position-specific oxidative modifications (8-oxoguanine) in tumor microRNAs are clinically associated with lower-grade gliomas and liver hepatocellular carcinoma.

8-oxoguanine modifications preferentially occur in the 5' end seed regions of microRNAs.
Specific modifications are linked to tumor suppression in lower-grade gliomas and tumor promotion in liver hepatocellular carcinoma.
Increased levels of 3oG-miR-122 and 4oG-let-7 are correlated with malignancy in liver cancer.
Stepwise oxidation of miR-122 from 3oG to 2,3oG alters its regulatory effects, potentially impacting liver cancer development.
Modulating these oxidative changes in mouse liver can reduce the risk of cancer induced by certain chemicals.

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

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

Abstract

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