Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid

Ban, J; Jug, G; Mestdagh, P; Schwentner, R; Kauer, M; Aryee, DN; Schaefer, KL; Nakatani, F; Scotlandi, K; Reiter, M; Strunk, D; Speleman, F; Vandesompele, J; Kovar, H.
Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma.
Oncogene. 2011; 30(18): 2173-2180. [OPEN ACCESS]
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Autor/innen der Med Uni Graz:
Strunk Dirk
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Abstract:
EWS-FLI1 is a chromosome translocation-derived chimeric transcription factor that has a central and rate-limiting role in the pathogenesis of Ewing's sarcoma. Although the EWS-FLI1 transcriptomic signature has been extensively characterized on the mRNA level, information on its impact on non-coding RNA expression is lacking. We have performed a genome-wide analysis of microRNAs affected by RNAi-mediated silencing of EWS-FLI1 in Ewing's sarcoma cell lines, and differentially expressed between primary Ewing's sarcoma and mesenchymal progenitor cells. Here, we report on the identification of hsa-mir-145 as the top EWS-FLI1-repressed microRNA. Upon knockdown of EWS-FLI1, hsa-mir-145 expression dramatically increases in all Ewing's sarcoma cell lines tested. Vice versa, ectopic expression of the microRNA in Ewing's sarcoma cell lines strongly reduced EWS-FLI1 protein, whereas transfection of an anti-mir to hsa-mir-145 increased the EWS-FLI1 levels. Reporter gene assays revealed that this modulation of EWS-FLI1 protein was mediated by the microRNA targeting the FLI1 3'-untranslated region. Mutual regulations of EWS-FLI1 and hsa-mir-145 were mirrored by an inverse correlation between their expression levels in four of the Ewing's sarcoma cell lines tested. Consistent with the role of EWS-FLI1 in Ewing's sarcoma growth regulation, forced hsa-mir-145 expression halted Ewing's sarcoma cell line growth. These results identify feedback regulation between EWS-FLI1 and hsa-mir-145 as an important component of the EWS-FLI1-mediated Ewing's sarcomagenesis that may open a new avenue to future microRNA-mediated therapy of this devastating malignant disease.
Find related publications in this database (using NLM MeSH Indexing)
Base Sequence -
DNA Primers -
Humans -
MicroRNAs - genetics
Oncogene Proteins, Fusion - genetics
Proto-Oncogene Protein c-fli-1 - genetics
RNA-Binding Protein EWS - genetics
Sarcoma, Ewing - genetics

Find related publications in this database (Keywords)
Ewing's sarcoma
microRNA
mir-145
EWS-FLI1
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