c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma
c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma
复制标题
c-Myc-miR-29c-REV3L 信号通路驱动胶质母细胞瘤中替莫唑胺耐药的获得。
DOI：
10.1093/brain/awv287
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发表时间：
2015-12-01
期刊：
影响因子：
14.5
通讯作者：
Wang, Huibo
中科院分区：
文献类型：
--
作者：
Luo, Hui;Chen, Zhengxin;Wang, Huibo
对替莫唑胺的耐药是多形性胶质母细胞瘤治疗的主要临床挑战，并且对替莫唑胺耐药的潜在机制仍然知之甚少。增强的DNA修复和诱变可以使肿瘤细胞存活，有助于耐药性和肿瘤复发。在这里，使用复发性替莫唑胺难治性胶质母细胞瘤标本，替莫唑胺耐药细胞和耐药异种移植模型，我们报告了miR-29 c通过c-Myc的丢失通过增强REV 3L介导的DNA修复和胶质母细胞瘤中的诱变来驱动替莫唑胺耐药的获得。重要的是，c-Myc/miR-29 c/REV 3L信号传导的破坏可能具有双重抗癌作用，使耐药肿瘤对治疗敏感，并防止获得性替莫唑胺耐药的出现。我们的研究结果表明，靶向c-Myc/miR-29 c/REV 3L信号通路是一种有前途的胶质母细胞瘤治疗方法，即使在复发性，治疗难治性环境中。
Resistance to temozolomide poses a major clinical challenge in glioblastoma multiforme treatment, and the mechanisms underlying the development of temozolomide resistance remain poorly understood. Enhanced DNA repair and mutagenesis can allow tumour cells to survive, contributing to resistance and tumour recurrence. Here, using recurrent temozolomide-refractory glioblastoma specimens, temozolomide-resistant cells, and resistant-xenograft models, we report that loss of miR-29c via c-Myc drives the acquisition of temozolomide resistance through enhancement of REV3L-mediated DNA repair and mutagenesis in glioblastoma. Importantly, disruption of c-Myc/miR-29c/REV3L signalling may have dual anticancer effects, sensitizing the resistant tumours to therapy as well as preventing the emergence of acquired temozolomide resistance. Our findings suggest a rationale for targeting the c-Myc/miR-29c/REV3L signalling pathway as a promising therapeutic approach for glioblastoma, even in recurrent, treatment-refractory settings.