Deng Yuan-Run, Wu Qiao-Zhi, Zhang Wan, Jiang Hui-Ping, Xu Cai-Qiu, Chen Shao-Cheng, Fan Jing, Guo Sui-Qun, Chen Xiao-Jing
Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical University, 183 Zhongshan Avenue West, Tianhe District, Guangzhou, 510630, P.R. China.
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
J Transl Med. 2025 Mar 14;23(1):328. doi: 10.1186/s12967-025-06350-4.
Radioresistance presents a major challenge in the treatment of cervical cancer (CC). Apoptotic tumor cells can create an "onco-regenerative niche," contributing to radioresistance. However, the intercellular signaling mechanisms mediating the transfer of radioresistance from apoptotic to surviving cancer cells remain unclear.
The role of apoptotic tumor cell-derived extracellular vesicles (apoEVs) in mediating radioresistance was investigated through integrated bioinformatics and experimental approaches. The GSE236738 dataset was analyzed to identify potential regulators, with subsequent validation of apoEV-MTA1 function using in vitro and in vivo models. Mechanistic studies focused on caspase-3 activation, p-STAT1 signaling pathway, and dormancy-associated protein networks. Furthermore, therapeutic strategies targeting MTA1 and its downstream signaling were evaluated for radiosensitization potential.
MTA1 was identified as a critical factor enriched in and transferred by apoEVs from apoptotic tumor cells to neighboring CC cells. Caspase-3 activation facilitated the nuclear export and encapsulation of MTA1 in apoEVs. Transferred MTA1 retained transcriptional activity, activated the p-STAT1 signaling pathway, and induced cellular dormancy via NR2F1, a key dormancy regulator, resulting in increased radioresistance. Knockdown of MTA1 in apoEVs or inhibition of p-STAT1 in recipient cells enhanced radiosensitivity. Furthermore, apoEV-MTA1 promoted tumor radioresistance and reduced survival rates in irradiated cervical cancer mouse model.
This study demonstrates that apoEV-MTA1 confers radioresistance in CC by promoting cellular dormancy via the p-STAT1/NR2F1 signaling axis. Targeting this pathway could improve radiosensitivity and provide a promising therapeutic strategy for CC patients.
放射抗性是宫颈癌（CC）治疗中的一个主要挑战。凋亡的肿瘤细胞可形成“肿瘤再生微环境”，导致放射抗性。然而，介导放射抗性从凋亡癌细胞向存活癌细胞转移的细胞间信号传导机制仍不清楚。
通过综合生物信息学和实验方法研究凋亡肿瘤细胞衍生的细胞外囊泡（apoEVs）在介导放射抗性中的作用。分析GSE236738数据集以鉴定潜在调节因子，随后使用体外和体内模型验证apoEV-MTA1功能。机制研究集中在半胱天冬酶-3激活、p-STAT1信号通路和与休眠相关的蛋白质网络。此外，评估了靶向MTA1及其下游信号的治疗策略的放射增敏潜力。
MTA1被确定为一个关键因素，其在凋亡肿瘤细胞的apoEVs中富集并从凋亡肿瘤细胞转移至邻近的CC细胞。半胱天冬酶-3激活促进了MTA1在apoEVs中的核输出和包裹。转移的MTA1保留转录活性，激活p-STAT1信号通路，并通过关键的休眠调节因子NR2F1诱导细胞休眠，从而导致放射抗性增加。敲低apoEVs中的MTA1或抑制受体细胞中的p-STAT1可增强放射敏感性。此外，apoEV-MTA1在受辐射的宫颈癌小鼠模型中促进肿瘤放射抗性并降低存活率。
本研究表明，apoEV-MTA1通过p-STAT1/NR2F1信号轴促进细胞休眠，从而赋予CC放射抗性。靶向该途径可提高放射敏感性，并为CC患者提供一种有前景的治疗策略。
