Format

Send to

Choose Destination
Oncogene. 2014 Oct 30;33(44):5183-92. doi: 10.1038/onc.2013.461. Epub 2013 Nov 4.

TMPRSS2-ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c.

Author information

1
Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
2
1] Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA [2] Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

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.

PMID:
24186205
PMCID:
PMC4009393
DOI:
10.1038/onc.2013.461
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center