Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1
Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1
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Mettl14通过Notch1的N-6-甲基腺苷抑制膀胱TIC自我更新和膀胱肿瘤发生
DOI：
10.1186/s12943-019-1084-1
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发表时间：
2019-11-25
期刊：
影响因子：
37.3
通讯作者：
Tian, Fengyan
中科院分区：
文献类型：
--
作者：
Gu, Chaohui;Wang, Zhiyu;Tian, Fengyan
背景N-6-甲基腺苷（m（6）A）是RNA最重要的修饰之一。膀胱癌是发达国家常见的癌症类型，每年有数十万膀胱癌患者死亡。材料与方法膀胱肿瘤组织中存在多种细胞，其中一小部分细胞具有自我更新和分化能力，称为肿瘤起始细胞（TIC）。膀胱TIC驱动膀胱肿瘤发生和转移，并且它们的活性受到精细调节。然而，N-6-甲基腺苷在膀胱TIC自我更新中的作用尚不清楚。结果膀胱肿瘤和膀胱TIC中N-6-甲基腺苷的含量明显降低。N-6-甲基腺苷水平与临床严重程度和结局相关。Mettl 14在膀胱癌和膀胱TIC中低表达。Mettl 14基因敲除促进膀胱TIC的增殖、自我更新、转移和肿瘤启动能力，而Mettl 14过表达则发挥相反的作用。Mettl 14和m（6）A修饰参与Notch 1 mRNA的RNA稳定性。Notch 1 m（6）A修饰抑制其RNA稳定性。Notch 1在膀胱肿瘤发生和膀胱TIC自我更新中起重要作用。结论本研究揭示了Mettl 14和N-6-甲基腺苷在膀胱肿瘤发生和膀胱TIC中的新作用，为膀胱TIC调控和N-6-甲基腺苷功能增加了新的层次。
Background N-6-methyladenosine (m(6)A) emerges as one of the most important modification of RNA. Bladder cancer is a common cancer type in developed countries, and hundreds of thousands of bladder cancer patients die every year. Materials and methods There are various cells in bladder tumor bulk, and a small population cells defined as tumor initiating cells (TIC) have self-renewal and differentiation capacities. Bladder TICs drive bladder tumorigenesis and metastasis, and their activities are fine regulated. However, the role of N-6-methyladenosine in bladder TIC self-renewal is unknown. Results Here, we found a decrease of N-6-methyladenosine in bladder tumors and bladder TICs. N-6-methyladenosine levels are related to clinical severity and outcome. Mettl14 is lowly expressed in bladder cancer and bladder TICs. Mettl14 knockout promotes the proliferation, self-renewal, metastasis and tumor initiating capacity of bladder TICs, and Mettl14 overexpression exerts an opposite role. Mettl14 and m(6)A modification participate in the RNA stability of Notch1 mRNA. Notch1 m(6)A modification inhibits its RNA stability. Notch1 plays an essential role in bladder tumorigenesis and bladder TIC self-renewal. Conclusion This work reveals a novel role of Mettl14 and N-6-methyladenosine in bladder tumorigenesis and bladder TICs, adding new layers for bladder TIC regulation and N-6-methyladenosine function.