c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma

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 t...

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Bibliographic Details
Published in:Brain (London, England : 1878) England : 1878), 2015-12, Vol.138 (Pt 12), p.3654-3672
Main Authors: Luo, Hui, Chen, Zhengxin, Wang, Shuai, Zhang, Rui, Qiu, Wenjin, Zhao, Lin, Peng, Chenghao, Xu, Ran, Chen, Wanghao, Wang, Hong-Wei, Chen, Yuanyuan, Yang, Jingmin, Zhang, Xiaotian, Zhang, Shuyu, Chen, Dan, Wu, Wenting, Zhao, Chunsheng, Cheng, Gang, Jiang, Tao, Lu, Daru, You, Yongping, Liu, Ning, Wang, Huibo
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Alkylating - pharmacology
Cell Line, Tumor
Dacarbazine - analogs & derivatives
Dacarbazine - pharmacology
DNA-Binding Proteins - metabolism
DNA-Directed DNA Polymerase - metabolism
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Gene Expression Regulation, Neoplastic - genetics
Glioblastoma - genetics
Glioblastoma - metabolism
Humans
Mice
MicroRNAs - metabolism
Proto-Oncogene Proteins c-myc - metabolism
Signal Transduction - drug effects
Signal Transduction - genetics
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Summary: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.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awv287