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Forschungsdatenbank PMU-SQQUID

Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing"s sarcoma.
Ban, J; Jug, G; Mestdagh, P; Schwentner, R; Kauer, M; Aryee, DNT; Schaefer, KL; Nakatani, F; Scotlandi, K; Reiter, M; Strunk, D; Speleman, F; Vandesompele, J; Kovar, H
ONCOGENE. 2011; 30(18): 2173-2180.
Originalarbeiten (Zeitschrift)

PMU-Autor/inn/en

Strunk Dirk

Abstract

EWS-FLI1 is a chromosome translocation-derived chimeric transcription factor that has a central and rate-limiting role in the pathogenesis of Ewingxxxs 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 Ewingxxxs sarcoma cell lines, and differentially expressed between primary Ewingxxxs 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 Ewingxxxs sarcoma cell lines tested. Vice versa, ectopic expression of the microRNA in Ewingxxxs 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 3xxx-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 Ewingxxxs sarcoma cell lines tested. Consistent with the role of EWS-FLI1 in Ewingxxxs sarcoma growth regulation, forced hsa-mir-145 expression halted Ewingxxxs 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 Ewingxxxs sarcomagenesis that may open a new avenue to future microRNA-mediated therapy of this devastating malignant disease. Oncogene (2011) 30, 2173-2180; doi:10.1038/onc.2010.581; published online 10 January 2011


Useful keywords (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)

Ewingxxxs sarcoma
microRNA
mir-145
EWS-FLI1