Insertional Mutagenesis Identifies a STAT3/Arid1b/ß-catenin Pathway Driving Neurofibroma Initiation.
Cell Rep
; 14(8): 1979-90, 2016 Mar 01.
Article
in En
| MEDLINE
| ID: mdl-26904939
ABSTRACT
To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/ß-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and ß-catenin activity. ß-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and ß-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3ß and the SWI/SNF gene Arid1b to increase ß-catenin. Knockdown of Arid1b or Gsk3ß in Stat3(fl/fl);Nf1(fl/fl);DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/ß-catenin pathway inhibitors in neurofibroma therapeutic trials.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peripheral Nervous System Neoplasms
/
Gene Expression Regulation, Neoplastic
/
Neurofibromatosis 1
/
DNA-Binding Proteins
/
STAT3 Transcription Factor
/
Beta Catenin
/
N-Terminal Acetyltransferase A
/
Carcinogenesis
Type of study:
Prognostic_studies
Language:
En
Journal:
Cell Rep
Year:
2016
Document type:
Article
Affiliation country:
United States