MiR-23a sensitizes nasopharyngeal carcinoma to irradiation by targeting IL-8/Stat3 pathway.
MiR-23a sensitizes nasopharyngeal carcinoma to irradiation by targeting IL-8/Stat3 pathway.
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MiR-23a 通过靶向 IL-8/Stat3 通路使鼻咽癌对放射敏感
DOI：
10.18632/oncotarget.5117
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Xiao ZQ
中科院分区：
文献类型：
--
作者：
Qu JQ;Yi HM;Ye X;Li LN;Zhu JF;Xiao T;Yuan L;Li JY;Wang YY;Feng J;He QY;Lu SS;Yi H;Xiao ZQ
放射抗性是鼻咽癌（NPC）治疗中的一个主要挑战，但对miRNA如何调控这一现象知之甚少。在本研究中，我们研究了miR-23 a在鼻咽癌放射抵抗中的功能和机制，miR-23 a是我们以前的微阵列分析中发现的在放射抵抗的鼻咽癌细胞中下调的miRNAs之一。我们观察到miR-23 a在放射抵抗的NPC组织中频繁下调，其下调与NPC放射抵抗和患者生存不良相关，并且是患者生存减少的独立预测因子。体外放射反应实验显示，miR-23 a表达的恢复可显著增加鼻咽癌细胞的放射敏感性。在小鼠模型中，治疗性给予miR-23 a阿戈米尔显著地使NPC异种移植物对辐射敏感。从机制上讲，我们发现减少的miR-23 a通过激活IL-8/Stat 3信号通路促进NPC细胞的辐射抗性。在放射抵抗的鼻咽癌组织中，IL-8和phospho-Stat 3水平升高，并与miR-23 a水平呈负相关。我们的数据表明，miR-23 a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/Stat 3信号转导增强NPC放射抗性，突出了miR-23 a/IL-8/Stat 3信号转导轴在NPC放射增敏中的治疗潜力。
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.