环状RNA与m6A修饰调控恶性肿瘤作用研究进展

Research progress of circular RNAs and N6-methyladenosine modifications in the regulation of malignant tumors

N6-甲基腺嘌呤(m6A)是真核生物RNA中最常见的表观遗传修饰,由甲基转移酶、去甲基化酶和阅读蛋白共同调控实现生物体内动态平衡及甲基化的可逆变化,影响RNA的剪接、加工、定位、转运、翻译和降解等过程,从而调控肿瘤的进展。环状RNA(circRNA)作为一种新型多功能非编码RNA,具有结构稳定、进化保守、高度丰富、组织特异性等特征,同时它可通过充当microRNA(miRNA)分子海绵、结合蛋白质、翻译蛋白和调控基因转录和剪接等方式参与调节多种生理病理活动,有望为肿瘤早期诊断和治疗提供新的分子标志物及潜在药物靶点。大量研究表明,m6A与circRNA可分别调控癌基因表达,且两者之间存在相互调节作用,m6A修饰可调节circRNA生物发生、核输出、降解、翻译和先天免疫,circRNA也可通过miRNA分子海绵或结合m6A修饰酶等机制调控m6A修饰,共同参与肿瘤细胞的增殖、迁移侵袭、干性、耐药性和免疫微环境等过程,这将有助于发现更多肿瘤研究的调节机制和治疗靶点。然而,鉴于m6A修饰和circRNA生物学的复杂性,许多研究仍有待阐明,如m6A检测技术尚不精确、m6A修饰的circRNA数据库仍为空缺、circRNA高效生产方法的开发和递送系统优化仍处于初级阶段等。因此,m6A修饰和circRNA相互作用网络尚需更深入研究。本文综述了circRNA的特征、形成机制及生物学功能,并综合阐述了m6A甲基化修饰基本概念和研究现状,总结分析m6A修饰和circRNA间的相互作用,及其对恶性肿瘤发生发展的影响,对两者临床应用价值和应用前景进行讨论,以期为肿瘤早期诊断、精准诊疗、预后判断与药物研发提供新思路。

N6-methyladenosine(m6A)is the most common epigenetic modification in eukaryotic RNAs,which is dynamically balanced and reversibly changed in organisms through the coordinated regulation of methyltransferases,demethylases,and reader proteins.It affects the splicing,processing,localization,transportation,translation,and degradation of RNAs,thereby regulating the progression of tumors.Circular RNAs(circRNAs),as the novel multifunctional non-coding RNAs,possess characteristics like structural stability,evolutionary conservation,high abundance,and tissue specificity.Additionally,they participate in regulating various physiological and pathological activities by serving as a sponge of microRNAs(miRNAs),binding proteins,translating proteins,and modulating gene transcription and splicing,and are expected to provide new molecular markers and potential drug targets for the early diagnosis and treatment of tumors.Numerous studies have indicated that m6A and circRNAs can independently regulate oncogene expressions,and there is mutual regulatory interaction between them.M6A modification can regulate circRNA biogenesis,nuclear export,degradation,translation,and innate immunity.Similarly,circRNAs can regulate m6A modification through mechanisms such as acting as a miRNA sponge or binding m6A modification enzymes.Both participate in processes such as proliferation,migration,invasion,stemness,drug resistance,and the immune microenvironment of tumor cells,which will help discover more regulatory mechanisms and therapeutic targets for tumor research.However,given the complexity of m6A modification and circRNA biology,many aspects of research still need to be clarified.For example,m6A detection technology is not yet accurate,the database of m6A-modified circRNAs is still lacking,and efficient production methods and delivery system optimization for circRNAs are still in the early stages of development.Therefore,further in-depth research is needed on the interaction network between m6A modification and circRNAs.This article reviews the characteristics,formation mechanisms,and biological functions of circRNAs,along with an in-depth discussion on the basic concepts and current research status of m6A methylation modification,and also summarizes and analyzes the interaction between m6A modification and circRNAs and their impact on the occurrence and development of malignant tumors,as well as discusses their clinical application value and prospects,aiming to offer new perspectives for early tumor diagnosis,precision treatment,prognosis assessment,and drug development.