REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells.
Neuro Oncol
; 19(4): 514-523, 2017 04 01.
Article
en En
| MEDLINE
| ID: mdl-28040710
ABSTRACT
Background:
Glioblastoma (GBM) is one of the most common, aggressive, and invasive human brain tumors. There are few reliable mechanism-based therapeutic approaches for GBM patients. The transcriptional repressor RE1 silencing transcriptional factor (REST) regulates the oncogenic properties of a class of GBM stem-like cells (high-REST [HR]-GSCs) in humans. However, it has been unclear whether REST represses specific targets to regulate specific oncogenic functions or represses all targets with overlapping functions in GSCs.Methods:
We used genome-wide, biochemical, and mouse intracranial tumorigenic assays to identify and determine functions of microRNA (miR) targets of REST in 2 independent HR-GSC lines.Results:
Here we show that REST represses 2 major miR gene targets in HR-GSCs miR-203, a new target, and miR-124, a known target. Gain of function of miR-124 or miR-203 in HR-GSCs increased survival in tumor-bearing mice. Importantly, the increased survival of tumor-bearing mice caused by knockdown of REST in HR-GSCs was reversed by double knockdown of REST and either miR-203 or miR-124, indicating that these 2 miRs are critical tumor suppressors that are repressed in REST-mediated tumorigenesis. We further show that while miR-124 and the REST-miR-124 pathways regulate self-renewal, apoptosis and invasion, miR-203 and the REST-miR-203 pathways regulate only invasion. We further identify and validate potential mRNA targets of miR-203 and miR-124 in REST-mediated HR-GSC tumor invasion.Conclusions:
These findings indicate that REST regulates its miR gene targets with overlapping functions and suggest how REST maintains oncogenic competence in GSCs. These mechanisms could potentially be utilized to block REST-mediated GBM tumorigenesis.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
/
Células Madre Neoplásicas
/
Neoplasias Encefálicas
/
Glioblastoma
/
MicroARNs
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Neuro Oncol
Asunto de la revista:
NEOPLASIAS
/
NEUROLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos