Exosomal transfer of miR-151a enhances chemosensitivity to temozolomide in drug-resistant glioblastoma
Exosomal transfer of miR-151a enhances chemosensitivity to temozolomide in drug-resistant glioblastoma
复制标题
miR-151a 的外泌体转移增强了耐药胶质母细胞瘤对替莫唑胺的化疗敏感性。
DOI：
10.1016/j.canlet.2018.08.004
复制
发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
You, Yongping
中科院分区：
文献类型：
--
作者：
Zeng, Ailiang;Wei, Zhiyun;You, Yongping
化疗耐药性减弱了替莫唑胺（TMZ）治疗多形性胶质母细胞瘤（GBM）的效果。来自TMZ抗性GBM细胞的miRNA的外泌体转移是否可以赋予TMZ抗性仍有待确定。使用qPCR测定两种TMZ抗性GBM细胞系中的miR-151 a表达。通过微阵列分析、生物信息学和进一步的RNA染色质免疫沉淀（RNA-ChIP）分析鉴定miR-151 a的直接靶点。我们表征了来自TMZ抗性细胞系、血清和脑脊液（CSF）的外泌体，并确定了来自TMZ抗性细胞的外泌体对受体GBM细胞的影响。miR-151 a的缺失导致TMZ耐药性的获得。恢复的miR-151 a表达通过抑制XRCC 4介导的DNA修复致敏TMZ抗性GBM细胞。TMZ耐药GBM细胞以外泌体miR-151 a丢失依赖性方式赋予受体TMZ敏感细胞TMZ化学抗性。从供体TMZ抗性细胞恢复外来体miR 151 a消除了由供体TMZ抗性细胞指导的化学抗性传播。CSF来源的外泌体含有反映GBM在miR-151 a表达水平方面的潜在化学抗性状态的miRNA特征。外泌体miR-151 a不仅是一种可以预测化疗反应的微创“液体活检”，而且也是治疗难治性GBM的一个有希望的治疗靶点。
Chemoresistance blunts the effect of Temozolomide (TMZ) in the treatment of glioblastoma multiforme (GBM). Whether exosomal transfer of miRNAs derived from TMZ-resistant GBM cells could confer TMZ resistance remains to be determined. qPCR was used to determine miR-151a expression in two TMZ-resistant GBM cell lines. The direct targets of miR-151a were identified by microarray assays, bioinformatics and further RNA chromatin immunoprecipitation (RNA-ChIP) assay. We characterized exosomes from TMZ-resistant cell lines, serum and cerebrospinal fluid (CSF) and determined the effect of exosomes from TMZ-resistant cells on recipient GBM cells. miR-151a loss drove the acquisition of TMZ resistance. Restored miR-151a expression sensitized TMZ-resistant GBM cells via inhibiting XRCC4-mediated DNA repair. TMZ-resistant GBM cells conferred TMZ chemoresistance to recipient TMZ-sensitive cells in an exosomal miR-151a loss-dependent manner. Restoration of exosomal miR151a from donor TMZ-resistant cells abolished the chemoresistance dissemination that was directed by donor TMZ-resistant cells. CSF-derived exosomes contained miRNA signatures reflective of the underlying chemoresistant status of GBMs in terms of miR-151a expression levels. Exosomal miR-151a is not only essentially a lessinvasive 'liquid biopsy' that might predict chemotherapy response, but also represents a promising therapeutic target for therapy-refractory GBMs.