韩国首尔大学Sung Wook Chi团队取得一项新突破。他们的研究发现miRNA种子中广泛存在的8-氧鸟嘌呤（o⁸G）修饰差异化调节氧化还原依赖性癌症的进展。相关论文于2023年9月7日发表于国际学术期刊《自然-细胞生物学》杂志。

基于测序中o⁸G诱导的鸟嘌呤-胸腺嘧啶（o⁸G>T）变异，研究人员在肿瘤microRNA中发现了广泛存在的位置特异性o⁸G，该氧化首先发生在具有簇状序列模式的5′末端种子区域（2-8位置）；在临床上与早期胶质瘤和肝细胞癌患者相关。研究人员发现miR-124（4o⁸G-miR-124）和4o⁸G-let-7位置的o⁸G能抑制早期胶质瘤，而3o⁸G-miR-122和4o⁸G-let-7通过调控靶致癌基因的转录组促进肝细胞癌进展。促进肿瘤的3o⁸G-miR-122会逐步氧化为抑制肿瘤的2，3o⁸G-miR-122，其在小鼠肝脏中的特异性调节有效地减弱了二乙基亚硝胺诱导的肝癌发生。

这些发现为o⁸G对microRNA的表观转录调控以及氧化还原变化诱导的重编程提供了见解，并暗示其对癌症治疗的潜能。

研究人员表示，氧化应激通过改变基因表达促进肿瘤发生。伴随氧化应激产生的修饰之一是8-氧鸟嘌呤，其可以通过o⁸G•A碱基配对改变RNA-RNA相互作用，但其调节作用仍然未知。

附：英文原文

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

Author: Eom, Sangkyeong, Peak, Jongjin, Park, Jongyeun, Ahn, Seung Hyun, Cho, You Kyung, Jeong, Yeahji, Lee, Hye-Sook, Lee, Jung, Ignatova, Elizaveta, Lee, Sung Eun, Hong, Yunji, Gu, Dowoon, Kim, Geun-Woo D., Lee, Dong Chan, Hahm, Ja Young, Jeong, Jaemin, Choi, Dongho, Jang, Eun-Sook, Chi, Sung Wook

Issue&Volume: 2023-09-07

Abstract: 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. Eom, Peak, Park, Ahn and colleagues reveal and provide a comprehensive resource of 8-oxoguanine modifications in tumour microRNAs and show how they differentially influence malignancy progression in gliomas and hepatocellular carcinoma.

DOI: 10.1038/s41556-023-01209-6

Source: https://www.nature.com/articles/s41556-023-01209-6