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MicroRNA expression profiling of Ewing sarcoma cell lines

ABSTRACT: Ewing’s sarcoma family tumors (ESFT) are the second most common bone malignancy in children and young adults, characterized by the expression of a unique chromosomal translocation, that in 85% of cases lead to the expression of the EWS-FLI-1 fusion protein. ESW-FLI-1 functions as an aberrant transcription factor that can both induce and suppress its target genes. We have recently demonstrated that microRNA (miRNA) 145 is a direct EWS-FLI-1 target implicated in ESFT development. Here, we use global miRNA array profiling to show that ESFT display a distinct miRNA signature characterized by the induction or repression of a limited number of miRNAs, including the oncogenic and tumor suppressor miRNA 17-92 and let-7 families, respectively. We demonstrate that repression of the let-7 family member let-7a may be due to direct binding of EWS-FLI-1 to the let-7a promoter and that it participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a repression enhances ESFT growth is shown to be the induction of its target gene HMGA2, as overexpression of let-7a or repression of HMGA2 blocked ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a that restored its expression in tumor cells and decreased HMGA2 expression inhibited ESFT growth in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as a promising new therapeutic target for one of the most aggressive pediatric malignancies.

OTHER RELATED OMICS DATASETS IN: PRJNA140303

ORGANISM(S): Mus musculus Rattus norvegicus synthetic construct Homo sapiens

PROVIDER: GSE29085 | GEO | 2011/12/27

SECONDARY ACCESSION(S): PRJNA140303

REPOSITORIES: GEO

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Gene expression analysis of human pediatric mesenchymal stem cells (hpMSCs) upon expression of EWS-FLI-1

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