Qu Hongke, Wang Yumin, Yan Qijia, Fan Chunmei, Zhang Xiangyan, Wang Dan, Guo Can, Chen Pan, Shi Lei, Liao Qianjin, Zhou Ming, Wang Fuyan, Zeng Zhaoyang, Xiang Bo, Xiong Wei
NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, China.
Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, China.
J Exp Clin Cancer Res. 2024 Apr 23;43(1):122. doi: 10.1186/s13046-024-03049-0.
Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear.
RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein.
We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5'-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma.
These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.
放射治疗是恶性肿瘤临床治疗的主要方法之一。鼻咽癌主要通过放射治疗，为研究癌症放射治疗耐药机制提供了宝贵模型。虽然一些报告表明环状RNA参与调节放射治疗耐药性，但其潜在机制仍不清楚。
采用RT-qPCR和原位杂交检测鼻咽癌组织样本中circCDYL2的表达水平。通过体外和体内功能实验证明circCDYL2对鼻咽癌放射治疗耐药性的影响。HR-GFP报告基因检测确定circCDYL2影响同源重组修复。采用RNA下拉、RIP、蛋白质免疫印迹、免疫荧光和多核糖体分析实验验证circCDYL2通过与EIF3D蛋白结合促进RAD51的翻译。
我们发现circCDYL2在鼻咽癌组织中高表达，且与预后不良密切相关。体外和体内实验表明，circCDYL2在促进鼻咽癌放射治疗耐药性方面起关键作用。我们的研究揭示了一种特定机制，即circCDYL2作为支架分子，将真核翻译起始因子3亚基D蛋白（EIF3D）募集到DNA损伤修复途径的关键成分RAD51 mRNA的5'-UTR，以促进RAD51翻译起始并增强同源重组修复能力，最终导致鼻咽癌放射治疗耐药。
这些发现确立了circCDYL2/EIF3D/RAD51轴在鼻咽癌放射治疗耐药中的新作用。我们的工作不仅阐明了潜在的分子机制，还突出了circCDYL2作为鼻咽癌治疗增敏靶点和有前景的预后分子标志物的潜力。
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