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

E L McKinsey1, J K Parrish, A E Irwin

  • 1Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Oncogene
|June 7, 2011
PubMed

Insights

Ewing sarcoma oncogenesis involves the EWS/Fli1 oncoprotein repressing tumor-suppressive microRNAs (miRs). These miRs normally inhibit the insulin-like growth factor (IGF) pathway, revealing a new therapeutic target for pediatric sarcoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MicroRNAs (miRs) are crucial gene regulators implicated in various diseases, including cancer.
  • Aberrant microRNA expression is common in cancers, but poorly understood in pediatric malignancies like Ewing sarcoma.
  • Ewing sarcoma is driven by EWS/Ets fusion proteins that act as transcriptional regulators.

Purpose of the Study:

  • To identify microRNAs regulated by the EWS/Fli1 oncoprotein in Ewing sarcoma.
  • To investigate the role of these microRNAs in oncogenesis and their connection to the insulin-like growth factor (IGF) signaling pathway.
  • To explore potential therapeutic strategies targeting this newly identified pathway.

Main Methods:

  • Stable silencing of the EWS/Fli1 fusion oncoprotein.
  • Global microRNA profiling to identify differentially expressed miRs.
  • Bioinformatic prediction of microRNA targets within the IGF signaling pathway.
  • Functional assays to assess microRNA effects on Ewing sarcoma cell growth and IGF pathway components.

Main Results:

  • EWS/Fli1 strongly represses a set of microRNAs (miR-100, miR-125b, miR-22, miR-221/222, miR-27a, miR-29a).
  • These repressed microRNAs target multiple pro-oncogenic components of the IGF pathway, including IGF-1, IGF-1 receptor, mTOR, and S6K1.
  • The identified microRNAs exhibit tumor-suppressive functions by inhibiting Ewing sarcoma cell growth.

Conclusions:

  • The EWS/Fli1 oncoprotein drives Ewing sarcoma by repressing tumor-suppressive microRNAs, leading to derepression of the IGF signaling pathway.
  • This novel mechanism highlights a critical role for microRNAs in Ewing sarcoma pathogenesis.
  • Targeting this microRNA-mediated regulation of IGF signaling presents a potential therapeutic avenue for Ewing sarcoma and other cancers with activated IGF pathways.

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