Abstract
Ewing's sarcoma family tumors (ESFT) are the second most common bone malignancy in children and young adults, characterized by unique chromosomal translocations that in 85% of cases lead to expression of the EWS-FLI-1 fusion protein. EWS-FLI-1 functions as an aberrant transcription factor that can both induce and suppress members of its target gene repertoire. We have recently demonstrated that EWS-FLI-1 can alter microRNA (miRNA) expression and that miRNA145 is a direct EWS-FLI-1 target whose suppression is implicated in ESFT development. Here, we use miRNA arrays to compare the global miRNA expression profile of human mesenchymal stem cells (MSC) and ESFT cell lines, and show that ESFT display a distinct miRNA signature that includes induction of the oncogenic miRNA 17–92 cluster and repression of the tumor suppressor let-7 family. We demonstrate that direct repression of let-7a by EWS-FLI-1 participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a expression regulates ESFT growth is shown to be mediated by its target gene HMGA2, as let-7a overexpression and HMGA2 repression both block ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a into ESFT-bearing mice restored its expression in tumor cells, decreased HMGA2 expression levels and resulted in ESFT growth inhibition in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as promising new therapeutic target for one of the most aggressive pediatric malignancies.
Highlights
Transformation and subsequent cancer development require genetic events in the form of point mutation, deletion or translocation of genes that either promote or control cell growth, proliferation and survival
To identify miRNAs that may be involved in Ewing’s sarcoma family tumors (ESFT) development we performed miRNA expression profiling of mesenchymal stem cells (MSC) and two ESFT cell lines (A673 and TC252)
Low expression of all the let-7 family members was observed in primary ESFT cells and ESFT cell lines compared to MSCs (Figure 1A), we focused our attention on let-7a because its repression has been shown to be directly implicated in the pathogenesis of several cancer types as well as in maintenance of breast cancer cancer stem cells (CSC) [15,26]
Summary
Transformation and subsequent cancer development require genetic events in the form of point mutation, deletion or translocation of genes that either promote or control cell growth, proliferation and survival. The effects of these genetic alterations are subject to modulation by epigenetic events whose contribution may be key to the establishment of the full fledged malignant phenotype. The miRNA guides RISC to complementary sequences within the 3`untranslated regions (UTR), introns and even exons of a wide range of target genes By binding to their complementary sequences, miRNAs destabilize the corresponding transcripts through mRNA degradation or reduced translation, leading to their silencing
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