氧化应激通过改变基因表达促进肿瘤发生。其中一种伴随的修饰物8-氧鸟嘌呤（o8G）可以通过 o8G•A 碱基配对改变 RNA-RNA 相互作用，但其调控作用仍然不清楚。基于测序中特征为 o8G 诱导的鸟嘌呤到胸腺嘧啶（o8G > T）变异，我们在肿瘤微小RNA中发现了广泛的位置特异性 o8G，其首选氧化于以序列模式聚集的 5' 端种子区域（2-8 位置），并与低级别胶质瘤和肝细胞肝癌患者有临床关联。我们验证了在 miR-124 的位置 4 上的 o8G（4o8G-miR-124）和 4o8G-let-7 可以抑制低级别胶质瘤，而 3o8G-miR-122 和 4o8G-let-7 可以促进肝细胞肝癌的恶性化，通过将靶转录组重定向到致癌的调控途径。由促进肿瘤的 3o8G-miR-122 逐步发生到抑制肿瘤的 2,3o8G-miR-122 的氧化过程发生，并且在小鼠肝脏中特异性调节有效地减轻了二乙基亚硝胺诱导的肝癌发生。这些发现为由氧化还原改变重编程的 microRNA 功能的表转录o8G 调控提供了资源和见解，暗示其在癌症治疗中的控制。© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.