miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1
miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1
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miR-125b抑制剂通过靶向Bak1增强胶质母细胞瘤干细胞对替莫唑胺的化疗敏感性
DOI：
10.1007/s13277-014-1821-4
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发表时间：
2014-07-01
期刊：
影响因子：
--
通讯作者：
Shi, Lei
中科院分区：
文献类型：
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作者：
Chen, Jian;Fu, Xingli;Shi, Lei
替莫唑胺（TMZ）是一种很有前途的治疗胶质母细胞瘤的化疗药物。然而，耐药性发展迅速，频率很高。胶质母细胞瘤干细胞（GSCs）对药物治疗产生耐药性被认为是其关键因素之一。GSC对TMZ耐药的机制尚不完全清楚。microRNAs（miRNAs）在肿瘤发生和耐药中发挥重要作用。先前的研究表明，miR-125 b是GSC分裂和使干细胞对化疗不敏感所必需的。因此，探索miR-125 b对TMZ处理的GSC的作用的功能和机制将是有价值的。在这项研究中，我们发现miR-125 b在TMZ耐药细胞中上调，抑制miR-125 b导致TMZ诱导的细胞毒性和凋亡显著增加，随后降低GSC对TMZ的耐药性。此外，我们证明了促凋亡Bcl-2拮抗剂killer 1（Bak 1）是miR-125 b的直接靶点。Bak 1的下调抑制TMZ诱导的细胞凋亡，并导致对TMZ的抗性增加。恢复Bak 1表达可恢复TMZ对GSC的敏感性。总之，我们的数据强烈支持miR-125 b通过靶向Bak 1表达在赋予TMZ抗性方面的重要作用。
Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly with a high frequency. Glioblastoma stem cells (GSCs) causing resistance to drug therapy were considered to be one of key factors. The mechanisms underlying GSCs resistance to TMZ are not fully understood. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. Previous study showed that miR-125b was necessary for GSCs fission and for making stem cells insensitive to chemotherapy. Thus, exploring the functions and mechanisms of miR-125b action on TMZ-treated GSCs would be valuable. In this study, we found that miR-125b was up-regulated in TMZ-resistant cells, inhibition of which caused a marked increase of TMZ-induced cytotoxicity and apoptosis and a subsequent decrease in the resistance to TMZ in GSCs. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) was a direct target of miR-125b. Down-regulation of Bak1 inhibited TMZ-induced apoptosis and led to an increased resistance to TMZ. Restoring Bak1 expression recovered TMZ sensitivity on GSCs. Taken together; our data strongly support an important role for miR-125b on conferring TMZ resistance through targeting Bak1 expression.