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A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs

Oncogene volume 30, pages 4910–4920 (2011)Cite this article

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Abstract

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with critical functions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences. However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven by EWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, all of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGF signaling.

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Acknowledgements

We wish to thank Steve Lessnick for Ewing sarcoma cell lines; James DeGregori and Yosef Refaeli for lentiviral and retroviral reagents; Lynne Bemis, Dawn Cochrane, Heide Ford, Jennifer Richer and Rajeev Vibhakar for helpful suggestions/discussions. Funding for this work was provided by Alex's Lemonade Stand Foundation for Childhood Cancer, the Boettcher Foundation's Webb-Waring Biomedical Research Program, and the University of Colorado Cancer Center and School of Medicine. These studies were inspired by the memory of Zeljko Nikolic.

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  1. H B Kern

    Present address: 4Present address: MST Program, University of Washington School of Medicine, Seattle, WA, USA,

  2. E L McKinsey and J K Parrish: These authors contributed equally to this work.

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  1. Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

    E L McKinsey, J K Parrish, A E Irwin, B F Niemeyer, H B Kern & P Jedlicka

  2. Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

    D K Birks

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McKinsey, E., Parrish, J., Irwin, A. et al. A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs. Oncogene 30, 4910–4920 (2011). https://doi.org/10.1038/onc.2011.197

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  • DOI: https://doi.org/10.1038/onc.2011.197

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