Insertional Mutagenesis Identifies a STAT3/Arid1b/ß-catenin Pathway Driving Neurofibroma Initiation.
Cell Rep
; 14(8): 1979-90, 2016 Mar 01.
Article
em 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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Neoplasias do Sistema Nervoso Periférico
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Regulação Neoplásica da Expressão Gênica
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Neurofibromatose 1
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Proteínas de Ligação a DNA
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Fator de Transcrição STAT3
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Beta Catenina
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Acetiltransferase N-Terminal A
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Carcinogênese
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos