PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation
Clin. transl. oncol. (Print)
; 14(3): 197-206, mar. 2012. tab, ilus
Artigo
em Inglês
| IBECS
| ID: ibc-126176
Biblioteca responsável:
ES1.1
Localização: BNCS
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 (AU)
Buscar no Google
Coleções:
Bases de dados nacionais
/
Espanha
Base de dados:
IBECS
Assunto principal:
Proteínas de Fusão Oncogênica
/
NF-kappa B
/
Rabdomiossarcoma Alveolar
/
Desenvolvimento Muscular
/
Mioblastos
/
Análise em Microsséries
Tipo de estudo:
Estudo prognóstico
Limite:
Animais
/
Feminino
/
Humanos
/
Masculino
Idioma:
Inglês
Revista:
Clin. transl. oncol. (Print)
Ano de publicação:
2012
Tipo de documento:
Artigo
Instituição/País de afiliação:
Columbia University/USA
/
Edith Cowan University/Australia
/
Memorial Sloan Kettering Cancer Center/USA