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Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs

(2013) ONCOGENE. 32(24). p.2927-2936
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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 30-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.
Keywords
TUMOR-SUPPRESSOR, methylation, PROMOTES TRANSFORMATION, tumor suppressor, neuroblastoma, SOX2, CELL DIFFERENTIATION, TRANSCRIPTION FACTOR, RETINOIC ACID, EXPRESSION, METHYLATION, GENE, PROLIFERATION, HUMAN HEPATOCELLULAR-CARCINOMA, miRNA

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Citation

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MLA
Das, S, K Bryan, PG Buckley, et al. “Modulation of Neuroblastoma Disease Pathogenesis by an Extensive Network of Epigenetically Regulated microRNAs.” ONCOGENE 32.24 (2013): 2927–2936. Print.
APA
Das, S, Bryan, K., Buckley, P., Piskareva, O., Bray, I., Foley, N., Ryan, J., et al. (2013). Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs. ONCOGENE, 32(24), 2927–2936.
Chicago author-date
Das, S, K Bryan, PG Buckley, O Piskareva, IM Bray, N Foley, J Ryan, et al. 2013. “Modulation of Neuroblastoma Disease Pathogenesis by an Extensive Network of Epigenetically Regulated microRNAs.” Oncogene 32 (24): 2927–2936.
Chicago author-date (all authors)
Das, S, K Bryan, PG Buckley, O Piskareva, IM Bray, N Foley, J Ryan, J Lynch, L Creevey, J Fay, S Prenter, J Koster, P van Sluis, R Versteeg, A Eggert, JH Schulte, A Schramm, Pieter Mestdagh, Jo Vandesompele, Franki Speleman, and RL Stallings. 2013. “Modulation of Neuroblastoma Disease Pathogenesis by an Extensive Network of Epigenetically Regulated microRNAs.” Oncogene 32 (24): 2927–2936.
Vancouver
1.
Das S, Bryan K, Buckley P, Piskareva O, Bray I, Foley N, et al. Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs. ONCOGENE. 2013;32(24):2927–36.
IEEE
[1]
S. Das et al., “Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs,” ONCOGENE, vol. 32, no. 24, pp. 2927–2936, 2013.
@article{3203418,
  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 30-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.},
  author       = {Das, S and Bryan, K and Buckley, PG and Piskareva, O and Bray, IM and Foley, N and Ryan, J and Lynch, J and Creevey, L and Fay, J and Prenter, S and Koster, J and van Sluis, P and Versteeg, R and Eggert, A and Schulte, JH and Schramm, A and Mestdagh, Pieter and Vandesompele, Jo and Speleman, Franki and Stallings, RL},
  issn         = {0950-9232},
  journal      = {ONCOGENE},
  keywords     = {TUMOR-SUPPRESSOR,methylation,PROMOTES TRANSFORMATION,tumor suppressor,neuroblastoma,SOX2,CELL DIFFERENTIATION,TRANSCRIPTION FACTOR,RETINOIC ACID,EXPRESSION,METHYLATION,GENE,PROLIFERATION,HUMAN HEPATOCELLULAR-CARCINOMA,miRNA},
  language     = {eng},
  number       = {24},
  pages        = {2927--2936},
  title        = {Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs},
  url          = {http://dx.doi.org/10.1038/onc.2012.311},
  volume       = {32},
  year         = {2013},
}

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