RNA N6-methyladenosine modification is required for miR-98/MYCN axis-mediated inhibition of neuroblastoma progression
RNA N6-methyladenosine modification is required for miR-98/MYCN axis-mediated inhibition of neuroblastoma progression
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DOI：
10.1038/s41598-020-64682-1
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发表时间：
2020-08-12
影响因子：
4.6
通讯作者：
Wang, Jinghua
中科院分区：
文献类型：
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作者：
Cheng, Junmei;Xu, Lingling;Wang, Jinghua
神经母细胞瘤是儿童交感神经系统最常见的恶性肿瘤之一。NB严重威胁患者的健康和生命。然而，世界各地的诊所都迫切需要更有效的诊断和治疗方法。MYCN被公认为NB高风险和不良结局的遗传生物标志物。miRNA是小RNA和miR-98，参与各种癌症的发病机制。miR-98在NB中的作用和机制仍有待进一步研究。我们发现miR-98在MYCN高表达的NB组织中表达减少，并且其下调与NB的不良预后相关。过表达miR-98可抑制NB细胞的增殖、迁移和侵袭。利用米兰达软件预测了miR-98在MYCN 3 ' -UTR中的可能结合位点，实验数据表明miR-98直接与MYCN 3 ' -UTR结合，降低MYCN的表达。MYCN的过表达挽救了NB中miR-98过表达引起的恶性表型降低。MYCN的3 ' -UTR中的N-6-甲基腺苷修饰促进其与miR-98的相互作用。这些数据共同表明，RNA m（6）A修饰是miR-98/MYCN轴介导的神经母细胞瘤进展抑制所必需的，并且miR-98可能是NB检测和治疗的新靶点。
Neuroblastoma (NB) is one of the most common malignant tumors of the sympathetic nervous system in childhood. NB severely threatens patient's health and life. However, more effective diagnosis and treatment methods are badly needed in clinics all over the world. MYCN is well recognized as a genetic biomarker of high risk and poor outcome in NB. miRNAs are small RNAs and miR-98 involved in the pathogenesis of various cancers. The role and mechanism of miR-98 in NB remains to be investigated. Here we found that miR-98 was decreased in human MYCN-high-expression NB tissues, and its down-regulation was associated with poor prognosis of NB. Over-expression of miR-98 inhibited cell proliferation, migration and invasion of NB cells. The analysis by employing the software of miRanda predicted the possible binding sites of miR-98 in the 3 ' -UTR of MYCN, and experimental data illustrated that miR-98 directly bound to MYCN 3 ' -UTR and decreased MYCN expression. Over-expression of MYCN rescued the decreased malignant phenotype caused by over-expression of miR-98 in NB. N-6-methyladenosine modification in 3 ' -UTR of MYCN promoted its interaction with miR-98. The data collectively demonstrated that RNA m(6)A modification was required for miR-98/MYCN axis-mediated inhibition of neuroblastoma progression, and miR-98 might be novel targets for NB detection and treatment.