Qu Jia-Quan, Yi Hong-Mei, Ye Xu, Li Li-Na, Zhu Jin-Feng, Xiao Ta, Yuan Li, Li Jiao-Yang, Wang Yuan-Yuan, Feng Juan, He Qiu-Yan, Lu Shan-Shan, Yi Hong, Xiao Zhi-Qiang
Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
The Higher Educational Key Laboratory for Cancer Proteomics and Translational Medicine of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Oncotarget. 2015 Sep 29;6(29):28341-56. doi: 10.18632/oncotarget.5117.
Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-23a in NPC radioresistance, one of downregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-23a was frequently downregulated in the radioresistant NPC tissues, and its decrement correlated with NPC radioresistance and poor patient survival, and was an independent predictor for reduced patient survival. In vitro radioresponse assays showed that restoration of miR-23a expression markedly increased NPC cell radiosensitivity. In a mouse model, therapeutic administration of miR-23a agomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we found that reduced miR-23a promoted NPC cell radioresistance by activating IL-8/Stat3 signaling. Moreover, the levels of IL-8 and phospho-Stat3 were increased in the radioresistance NPC tissues, and negatively associated with miR-23a level. Our data demonstrate that miR-23a is a critical determinant of NPC radioresponse and prognostic predictor for NPC patients, and its decrement enhances NPC radioresistance through activating IL-8/Stat3 signaling, highlighting the therapeutic potential of miR-23a/IL-8/Stat3 signaling axis in NPC radiosensitization.
放射抗性是鼻咽癌（NPC）治疗中的一个主要挑战，但关于miRNA如何调节这一现象却知之甚少。在本研究中，我们调查了miR-23a在NPC放射抗性中的功能和机制，miR-23a是我们之前通过微阵列分析在放射抗性NPC细胞中鉴定出的下调miRNA之一。我们观察到miR-23a在放射抗性NPC组织中经常下调，其减少与NPC放射抗性和患者预后不良相关，并且是患者生存率降低的独立预测因子。体外放射反应试验表明，恢复miR-23a表达可显著提高NPC细胞的放射敏感性。在小鼠模型中，治疗性给予miR-23a激动剂可显著使NPC异种移植瘤对辐射敏感。机制上，我们发现miR-23a减少通过激活IL-8/Stat3信号通路促进NPC细胞放射抗性。此外，放射抗性NPC组织中IL-8和磷酸化Stat3水平升高，且与miR-23a水平呈负相关。我们的数据表明，miR-23a是NPC放射反应的关键决定因素和NPC患者的预后预测因子，其减少通过激活IL-8/Stat3信号通路增强NPC放射抗性，突出了miR-23a/IL-8/Stat3信号轴在NPC放射增敏中的治疗潜力。
