Radiation-induced extracellular vesicle (EV) release of miR-603 promotes IGF1-mediated stem cell state in glioblastomas.
Animals
Brain Neoplasms
/ genetics
Cell Line, Tumor
Cell Survival
/ radiation effects
DNA Modification Methylases
/ genetics
DNA Repair
/ genetics
DNA Repair Enzymes
/ genetics
Extracellular Vesicles
/ genetics
Gamma Rays
Gene Expression Regulation, Neoplastic
Glioblastoma
/ genetics
Histones
/ genetics
Humans
Insulin-Like Growth Factor I
/ genetics
Isocitrate Dehydrogenase
/ genetics
Male
Mice
Mice, Nude
MicroRNAs
/ genetics
Neoplastic Stem Cells
/ metabolism
Radiation Tolerance
/ genetics
Receptor, IGF Type 1
/ genetics
Signal Transduction
Survival Analysis
Tumor Suppressor Proteins
/ genetics
Xenograft Model Antitumor Assays
Acquired radiation resistance
Extracellular vesicles
Glioblastoma stem-cell state
IGF1
MGMT
miR-603
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2020
May 2020
Historique:
received:
10
09
2019
revised:
06
03
2020
accepted:
11
03
2020
pubmed:
4
5
2020
medline:
2
4
2021
entrez:
4
5
2020
Statut:
ppublish
Résumé
Recurrence after radiation therapy is nearly universal for glioblastomas, the most common form of adult brain cancer. The study aims to define clinically pertinent mechanisms underlying this recurrence. microRNA (miRNA) profiling was performed using matched pre- and post-radiation treatment glioblastoma specimens from the same patients. All specimens harbored unmethylated O While nearly all miRNAs remained unchanged after treatment, decreased levels of few, select miRNAs in the post-treatment specimens were observed, the most notable of which involved miR-603. Unbiased profiling of miR-603 targets revealed insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R). Ionizing radiation (IR) induced cellular export of miR-603 through extracellular vesicle (EV) release, thereby de-repressing IGF1 and IGF1R. This de-repression, in turn, promoted cancer stem-cell (CSC) state and acquired radiation resistance in glioblastomas. Export of miR-603 additionally de-repressed MGMT, a DNA repair protein responsible for detoxifying DNA alkylating agents, to promote cross-resistance to these agents. Ectopic miR-603 expression overwhelmed cellular capacity for miR-603 export and synergized with the tumoricidal effects of IR and DNA alkylating agents. Profiling of matched pre- and post-treatment glioblastoma specimens revealed altered homeostasis of select miRNAs in response to radiation. Radiation-induced EV export of miR-603 simultaneously promoted the CSC state and up-regulated DNA repair to promote acquired resistance. These effects were abolished by exogenous miR-603 expression, suggesting potential for clinical translation. NIH 1R01NS097649-01, 9R44GM128223-02, 1R01CA240953-01, the Doris Duke Charitable Foundation Clinical Scientist Development Award, The Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (C.C.C).
Sections du résumé
BACKGROUND
BACKGROUND
Recurrence after radiation therapy is nearly universal for glioblastomas, the most common form of adult brain cancer. The study aims to define clinically pertinent mechanisms underlying this recurrence.
METHODS
METHODS
microRNA (miRNA) profiling was performed using matched pre- and post-radiation treatment glioblastoma specimens from the same patients. All specimens harbored unmethylated O
FINDINGS
RESULTS
While nearly all miRNAs remained unchanged after treatment, decreased levels of few, select miRNAs in the post-treatment specimens were observed, the most notable of which involved miR-603. Unbiased profiling of miR-603 targets revealed insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R). Ionizing radiation (IR) induced cellular export of miR-603 through extracellular vesicle (EV) release, thereby de-repressing IGF1 and IGF1R. This de-repression, in turn, promoted cancer stem-cell (CSC) state and acquired radiation resistance in glioblastomas. Export of miR-603 additionally de-repressed MGMT, a DNA repair protein responsible for detoxifying DNA alkylating agents, to promote cross-resistance to these agents. Ectopic miR-603 expression overwhelmed cellular capacity for miR-603 export and synergized with the tumoricidal effects of IR and DNA alkylating agents.
INTERPRETATION
CONCLUSIONS
Profiling of matched pre- and post-treatment glioblastoma specimens revealed altered homeostasis of select miRNAs in response to radiation. Radiation-induced EV export of miR-603 simultaneously promoted the CSC state and up-regulated DNA repair to promote acquired resistance. These effects were abolished by exogenous miR-603 expression, suggesting potential for clinical translation.
FUNDING
BACKGROUND
NIH 1R01NS097649-01, 9R44GM128223-02, 1R01CA240953-01, the Doris Duke Charitable Foundation Clinical Scientist Development Award, The Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (C.C.C).
Identifiants
pubmed: 32361246
pii: S2352-3964(20)30111-0
doi: 10.1016/j.ebiom.2020.102736
pmc: PMC7195524
pii:
doi:
Substances chimiques
H2AX protein, human
0
Histones
0
IGF1 protein, human
0
IGF1R protein, human
0
MIRN603 microRNA, human
0
MicroRNAs
0
Tumor Suppressor Proteins
0
Insulin-Like Growth Factor I
67763-96-6
Isocitrate Dehydrogenase
EC 1.1.1.41
DNA Modification Methylases
EC 2.1.1.-
MGMT protein, human
EC 2.1.1.63
Receptor, IGF Type 1
EC 2.7.10.1
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
102736Subventions
Organisme : NINDS NIH HHS
ID : R01 NS080939
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS097649
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest B.S.C. and C.C.C. received personal fees from Tocagen Co. Other authors declare no conflicts of interest.
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