TMPRSS2-ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c.
Oncogene
; 33(44): 5183-92, 2014 Oct 30.
Article
em En
| MEDLINE
| ID: mdl-24186205
ABSTRACT
Chromosomal translocations that juxtapose the androgen-sensitive transmembrane protease, serine 2 (TMPRSS2) gene promoter to the oncogenic ETS-family transcription factor ERG result in excessive ERG overexpression in approximately 50% of prostate cancer (PCa) patients. Although numerous studies have investigated ERG-downstream genes, such studies have not attempted to examine miRNAs, which however are emerging to be important regulators of cancer. Through bioinformatics analysis of ChIP-Seq ERG data and miRNA expression profiling data we nominated miR-200c as a direct target of ERG. Experimentation of PCa cells with ERG overexpression or knockdown demonstrated that ERG directly repressed miR-200c expression by physically binding to the erythroblast transformation-specific (ETS) motif within its promoter. Consequently, miR-200c was downregulated in ERG-positive PCa, and miR-200c target gene expression was restored. In addition, the expression pattern of miR-200c target genes predicted ERG status in clinical PCa specimens. Furthermore, miR-200c was found to be important in modulating ZEB1 upregulation by ERG. Most importantly, miR-200c reconstitution fully reversed ERG-induced epithelial-to-mesenchymal transition (EMT), cell migration and invasion. Therefore, our study report miR-200c as the first miRNA target of ERG and a critical inhibitor of PCa cell motility. Therapeutic delivery of miR-200c may provide personalized treatment for patients with the molecular subtype of PCa that harbors TMPRSS2-ERG gene fusions.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Proteínas de Fusão Oncogênica
/
MicroRNAs
Tipo de estudo:
Prognostic_studies
Limite:
Humans
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Male
Idioma:
En
Revista:
Oncogene
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos