Shi Junyu, Rui Xiaohui, Han Chunxiao, Wang Chaoping, Xu Lei, Jiang Xiping
Department of Gynecology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, PR China.
Cell Death Discov. 2023 Jul 20;9(1):253. doi: 10.1038/s41420-023-01557-0.
Circular RNAs (circRNAs) and N-methyladenosine (mA) have been shown to play an increasingly critical role in the development of different cancers. However, there is limited evidence on how circRNAs and mA interact to affect the radiosensitivity of cervical cancer (CC). This study provides a mechanistic understanding of the novel mA-regulated circRNF13 in enhancing radioresistance in CC.
Differentially expressed circRNAs were identified from radiosensitive and radioresistant CC tissues. Meanwhile, these circRNAs were subjected to methylated RNA immunoprecipitation (Me-RIP). Finally, the effects of these circRNAs on radiosensitivity were characterized.
CircRNF13 was poorly expressed in CC patients that were sensitive to concurrent radiochemotherapy. Experiments conducted both in vitro and in vivo confirmed that the knockdown of circRNF13 potentiated the radiosensitivity of CC cells. Further mechanistic studies revealed that METTL3/YTHDF2 promoted the degradation of circRNF13 and subsequently affected the stability of CXC motif chemokine ligand 1 (CXCL1), ultimately enhancing the radiosensitivity of CC cells.
This study identified circRNF13 as a novel mA-modified circRNA and validated the METTL3/YTHDF2/circRNF13/CXCL1 axis as a potential target for CC radiotherapy.
环状RNA（circRNAs）和N-甲基腺苷（m⁶A）已被证明在不同癌症的发展中发挥着越来越关键的作用。然而，关于circRNAs和m⁶A如何相互作用以影响宫颈癌（CC）的放射敏感性的证据有限。本研究提供了一种机制性的理解，即新型m⁶A调控的circRNF13在增强CC放射抗性中的作用。
从放射敏感和放射抗性的CC组织中鉴定出差异表达的circRNAs。同时，对这些circRNAs进行甲基化RNA免疫沉淀（Me-RIP）。最后，表征这些circRNAs对放射敏感性的影响。
circRNF13在对同步放化疗敏感的CC患者中表达较低。体外和体内实验均证实，敲低circRNF13可增强CC细胞的放射敏感性。进一步的机制研究表明，METTL3/YTHDF2促进circRNF13的降解，随后影响CXC基序趋化因子配体-1（CXCL1）的稳定性，最终增强CC细胞的放射敏感性。
本研究将circRNF13鉴定为一种新型的m⁶A修饰的circRNA，并验证了METTL3/YTHDF2/circRNF13/CXCL1轴作为CC放疗的潜在靶点。
