PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation
Clin. transl. oncol. (Print)
; 14(3): 197-206, mar. 2012. tab, ilus
Article
in En
| IBECS
| ID: ibc-126176
Responsible library:
ES1.1
Localization: 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)
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Collection:
06-national
/
ES
Database:
IBECS
Main subject:
Oncogene Proteins, Fusion
/
NF-kappa B
/
Rhabdomyosarcoma, Alveolar
/
Muscle Development
/
Myoblasts
/
Microarray Analysis
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Clin. transl. oncol. (Print)
Year:
2012
Document type:
Article