PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation.
Clin Transl Oncol
; 14(3): 197-206, 2012 Mar.
Article
em En
| MEDLINE
| ID: mdl-22374423
ABSTRACT
OBJECTIVE:
Alveolar rhabdomyosarcomas (ARMS) are characterised by a PAX3/7-FKHR translocation, which is presumed to promote a differentiation arrest in the myogenic lineage, in which setting secondary genetic events occur, resulting in sarcomagenesis. The aim of this study was to identify the mechanism by which PAX3/7-FKHR expression results in a myogenic differentiation block, as discrete from the secondary genetic events that complete the sarcomagenic process.METHODS:
We performed a novel differential gene expression analysis comparing normal mesenchymal stem cells with previously generated non-tumorigenic mesenchymal stem cells expressing the PAX7-FKHR fusion gene, as well as with a known tumorigenic, PAX7-FKHR-expressing ARMS cell line, CW9019.RESULTS:
This novel analysis uncovered the upregulation of the NF-kappaB pathway as a function of PAX3/7-FKHR expression, but distinct from the secondary sarcomagenic process; thus implicating NF-kappaB as a mediator of the PAX3/7-FKHR differentiation block. We further show that NF-kappaB activity is upregulated in PAX7-FKHR cells when compared to parental MSCs due to upregulation of the PI3K/AKT pathway. In addition we show that NF-kappaB inhibits myogenesis via activation of cyclinD1/ cdk4 complexes, which sequester MyoD1, a key myogenic transcription factor.CONCLUSIONS:
Our results highlight the importance of the NF-kappaB pathway in myogenesis and sarcomagenesis and suggest that this pathway may be one of the potential therapeutic targets in the treatment of ARMS.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Fusão Oncogênica
/
NF-kappa B
/
Desenvolvimento Muscular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article