title: c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma.
abstract: 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.
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Luo
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 2 Department of Haematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Qiu
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Chenghao
authors.initials: C
authors.lastname: Peng
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Xu
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wanghao
authors.initials: W
authors.lastname: Chen
authors.affiliation: 3 Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
authors.affiliation: 4 Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo 00015, Italy.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 5 State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes for Biomedical Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Yang
authors.affiliation: 6 Department of Molecular Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 7 School of Radiation Medicine and Protection, Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 8 Department of Immunology, Genetics and Pathology, Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: 9 Beyster Center for Genomics of Psychiatric Diseases, Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.affiliation: 10 Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing 100050, China 11 Chinese Glioma Cooperative Group (CGCG).
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: 5 State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes for Biomedical Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 11 Chinese Glioma Cooperative Group (CGCG).
authors.forename: Yongping
authors.initials: Y
authors.lastname: You
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 11 Chinese Glioma Cooperative Group (CGCG) hbwang@njmu.edu.cn liuning0853@yahoo.com.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 11 Chinese Glioma Cooperative Group (CGCG) hbwang@njmu.edu.cn liuning0853@yahoo.com.cn.
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C532045:MIRN29a microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D003606:Dacarbazine; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human; D000077204:Temozolomide
keywords: c-Myc/miR-29c/REV3L signalling; glioblastoma; temozolomide resistance