Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-01-10

AUTHORS

J Ban, G Jug, P Mestdagh, R Schwentner, M Kauer, D N T Aryee, K-L Schaefer, F Nakatani, K Scotlandi, M Reiter, D Strunk, F Speleman, J Vandesompele, H Kovar

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. More... »

PAGES

2173-2180

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2010.581

DOI

http://dx.doi.org/10.1038/onc.2010.581

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1043393653

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21217773


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24 schema:description 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.
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30 schema:keywords EWS-FLI1
31 EWS-FLI1 protein
32 Ewing
33 Ewing sarcomagenesis
34 Ewing's sarcoma
35 Ewing's sarcoma cell lines
36 FLI1
37 Primary Ewing's
38 RNA expression
39 RNAi-mediated silencing
40 analysis
41 assays
42 avenues
43 cell line growth
44 cell lines
45 cells
46 chimeric transcription factor
47 components
48 correlation
49 devastating malignant disease
50 disease
51 ectopic expression
52 expression
53 expression levels
54 factors
55 feedback loop
56 feedback regulation
57 gene assay
58 genome-wide analysis
59 growth
60 growth regulation
61 hsa-mir-145
62 identification
63 impact
64 important component
65 information
66 inverse correlation
67 knockdown
68 levels
69 line growth
70 lines
71 loop
72 mRNA levels
73 malignant disease
74 mesenchymal progenitor cells
75 miR
76 microRNAs
77 modulation
78 mutual regulation
79 new avenues
80 non-coding RNA expression
81 pathogenesis
82 positive feedback loop
83 progenitor cells
84 protein
85 rate-limiting role
86 region
87 regulation
88 reporter gene assay
89 results
90 role
91 sarcoma
92 sarcoma cell lines
93 sarcomagenesis
94 signatures
95 silencing
96 therapy
97 transcription factors
98 transcriptomic signatures
99 transfection
100 vice
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