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2011 ; 30
(49
): 4910-20
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A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by
EWS/Fli1-regulated microRNAs
#MMPMID21643012
McKinsey EL
; Parrish JK
; Irwin AE
; Niemeyer BF
; Kern HB
; Birks DK
; Jedlicka P
Oncogene
2011[Dec]; 30
(49
): 4910-20
PMID21643012
show ga
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.
|*Signal Transduction
[MESH]
|Base Sequence
[MESH]
|Cell Line, Tumor
[MESH]
|Gene Silencing
[MESH]
|Humans
[MESH]
|MicroRNAs/genetics/*metabolism
[MESH]
|Oligonucleotide Array Sequence Analysis
[MESH]
|Proto-Oncogene Protein c-fli-1/deficiency/genetics/*metabolism
[MESH]
|RNA-Binding Protein EWS/deficiency/genetics/*metabolism
[MESH]