Targeting radiation-tolerant persister cells as a strategy for inhibiting radioresistance and recurrence in glioblastoma.
Neuro Oncol
; 24(7): 1056-1070, 2022 07 01.
Article
en En
| MEDLINE
| ID: mdl-34905060
ABSTRACT
BACKGROUND:
Compelling evidence suggests that glioblastoma (GBM) recurrence results from the expansion of a subset of tumor cells with robust intrinsic or therapy-induced radioresistance. However, the mechanisms underlying GBM radioresistance and recurrence remain elusive. To overcome obstacles in radioresistance research, we present a novel preclinical model ideally suited for radiobiological studies.METHODS:
With this model, we performed a screen and identified a radiation-tolerant persister (RTP) subpopulation. RNA sequencing was performed on RTP and parental cells to obtain mRNA and miRNA expression profiles. The regulatory mechanisms among NF-κB, YY1, miR-103a, XRCC3, and FGF2 were investigated by transcription factor activation profiling array analysis, chromatin immunoprecipitation, western blot analysis, luciferase reporter assays, and the MirTrap system. Transferrin-functionalized nanoparticles (Tf-NPs) were employed to improve blood-brain barrier permeability and RTP targeting.RESULTS:
RTP cells drive radioresistance by preferentially activating DNA damage repair and promoting stemness. Mechanistic investigations showed that continual radiation activates the NF-κB signaling cascade and promotes nuclear translocation of p65, leading to enhanced expression of YY1, the transcription factor that directly suppresses miR-103a transcription. Restoring miR-103a expression under these conditions suppressed the FGF2-XRCC3 axis and decreased the radioresistance capability. Moreover, Tf-NPs improved radiosensitivity and provided a significant survival benefit.CONCLUSIONS:
We suggest that the NF-κB-YY1-miR-103a regulatory axis is indispensable for the function of RTP cells in driving radioresistance and recurrence. Thus, our results identified a novel strategy for improving survival in patients with recurrent/refractory GBM.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Glioblastoma
/
MicroARNs
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Neuro Oncol
Asunto de la revista:
NEOPLASIAS
/
NEUROLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
China