Title |
Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs
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Published in |
Oncogene, July 2012
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DOI | 10.1038/onc.2012.311 |
Pubmed ID | |
Authors |
S Das, K Bryan, P G Buckley, O Piskareva, I M Bray, N Foley, J Ryan, J Lynch, L Creevey, J Fay, S Prenter, J Koster, P van Sluis, R Versteeg, A Eggert, J H Schulte, A Schramm, P Mestdagh, J Vandesompele, F Speleman, R L Stallings |
Abstract |
MicroRNAs (miRNAs) contribute to the pathogenesis of many forms of cancer, including the pediatric cancer neuroblastoma, but the underlying mechanisms leading to altered miRNA expression are often unknown. Here, a novel integrated approach for analyzing DNA methylation coupled with miRNA and mRNA expression data sets identified 67 epigenetically regulated miRNA in neuroblastoma. A large proportion (42%) of these miRNAs was associated with poor patient survival when underexpressed in tumors. Moreover, we demonstrate that this panel of epigenetically silenced miRNAs targets a large set of genes that are overexpressed in tumors from patients with poor survival in a highly redundant manner. The genes targeted by the epigenetically regulated miRNAs are enriched for a number of biological processes, including regulation of cell differentiation. Functional studies involving ectopic overexpression of several of the epigenetically silenced miRNAs had a negative impact on neuroblastoma cell viability, providing further support to the concept that inactivation of these miRNAs is important for neuroblastoma disease pathogenesis. One locus, miR-340, induced either differentiation or apoptosis in a cell context dependent manner, indicating a tumor suppressive function for this miRNA. Intriguingly, it was determined that miR-340 is upregulated by demethylation of an upstream genomic region that occurs during the process of neuroblastoma cell differentiation induced by all-trans retinoic acid (ATRA). Further biological studies of miR-340 revealed that it directly represses the SOX2 transcription factor by targeting of its 3'-untranslated region, explaining the mechanism by which SOX2 is downregulated by ATRA. Although SOX2 contributes to the maintenance of stem cells in an undifferentiated state, we demonstrate that miR-340-mediated downregulation of SOX2 is not required for ATRA induced differentiation to occur. In summary, our results exemplify the dynamic nature of the miRNA epigenome and identify a remarkable network of miRNA/mRNA interactions that significantly contribute to neuroblastoma disease pathogenesis. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United States | 1 | 2% |
Sweden | 1 | 2% |
Germany | 1 | 2% |
Switzerland | 1 | 2% |
Unknown | 58 | 94% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 16 | 26% |
Student > Ph. D. Student | 10 | 16% |
Student > Bachelor | 8 | 13% |
Student > Master | 7 | 11% |
Professor > Associate Professor | 4 | 6% |
Other | 8 | 13% |
Unknown | 9 | 15% |
Readers by discipline | Count | As % |
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Agricultural and Biological Sciences | 20 | 32% |
Biochemistry, Genetics and Molecular Biology | 13 | 21% |
Medicine and Dentistry | 11 | 18% |
Computer Science | 2 | 3% |
Neuroscience | 2 | 3% |
Other | 5 | 8% |
Unknown | 9 | 15% |