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Dickkopf-3 is regulated by the MYCN-induced miR-17-92 cluster in neuroblastoma

Sara De Brouwer UGent, Pieter Mestdagh UGent, Irina Lambertz UGent, Filip Pattyn UGent, Anne De Paepe UGent, Frank Westermann, Christina Schroeder, Johannes H Schulte, Alexander Schramm and Katleen De Preter UGent, et al. (2012) INTERNATIONAL JOURNAL OF CANCER. 130(11). p.2591-2598
abstract
Neuroblastoma (NB) is a paediatric tumour with a remarkable diverse clinical behaviour. Approximately half of the high stage aggressive tumours are characterized by MYCN gene amplification but our understanding of the role of MYCN in NB oncogenesis is incomplete. Previous studies have shown that MYCN expression is inversely correlated with expression of Dickkopf-3 (DKK3), a gene encoding an extracellular protein with presumed tumour suppressor activity, but direct MYCN regulation of DKK3 was excluded leaving the mechanism of regulation unexplained. Given the recently established role of MYCN-regulated miRNAs in downregulation of protein-coding genes and predicted seeds for miR-17-92 cluster members within the DKK3 3'UTR, we hypothesized that this mechanism would act in MYCN regulation of DKK3. To investigate this, we used a validated miR-17-92-inducible cellular system and could demonstrate robust downregulation of DKK3 mRNA and protein levels upon miR-17-92 overexpression. Next, two of the three predicted miRNAs, miR-19b and miR-92a, were shown to lower DKK3 protein levels, in addition to measurable DKK3 mRNA knock-down by miR-92a. Direct interaction between miR-19b or miR-92a and the 3'UTR of DKK3 was validated using luciferase reporter assays. In conclusion, this study demonstrates that the MYCN-induced downregulation of DKK3 results from direct upregulation of miR-17-92 components effecting both DKK3 mRNA stability and translation which further contributes to the pleiotropic oncogenic effect of elevated MYCN levels. The strict MYCN-mediated regulation of DKK3 is suggestive for an important downstream function of the MYCN protein and thus warrants further investigations to unravel the role of DKK3 in NB.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
dickkopf-3, neuroblastoma, miR-17-92 cluster, N-MYC, RNA INTERFERENCE, PROSTATE-CANCER, DOWN-REGULATION, BETA-CATENIN, CELL-CYCLE, EXPRESSION, GENE, REIC/DKK-3, TARGET
journal title
INTERNATIONAL JOURNAL OF CANCER
Int. J. Cancer
volume
130
issue
11
pages
2591 - 2598
Web of Science type
Article
Web of Science id
000302013200012
JCR category
ONCOLOGY
JCR impact factor
6.198 (2012)
JCR rank
23/196 (2012)
JCR quartile
1 (2012)
ISSN
0020-7136
DOI
10.1002/ijc.26295
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2059820
handle
http://hdl.handle.net/1854/LU-2059820
date created
2012-03-05 15:24:15
date last changed
2012-09-19 13:57:15
@article{2059820,
  abstract     = {Neuroblastoma (NB) is a paediatric tumour with a remarkable diverse clinical behaviour. Approximately half of the high stage aggressive tumours are characterized by MYCN gene amplification but our understanding of the role of MYCN in NB oncogenesis is incomplete. Previous studies have shown that MYCN expression is inversely correlated with expression of Dickkopf-3 (DKK3), a gene encoding an extracellular protein with presumed tumour suppressor activity, but direct MYCN regulation of DKK3 was excluded leaving the mechanism of regulation unexplained. Given the recently established role of MYCN-regulated miRNAs in downregulation of protein-coding genes and predicted seeds for miR-17-92 cluster members within the DKK3 3'UTR, we hypothesized that this mechanism would act in MYCN regulation of DKK3. To investigate this, we used a validated miR-17-92-inducible cellular system and could demonstrate robust downregulation of DKK3 mRNA and protein levels upon miR-17-92 overexpression. Next, two of the three predicted miRNAs, miR-19b and miR-92a, were shown to lower DKK3 protein levels, in addition to measurable DKK3 mRNA knock-down by miR-92a. Direct interaction between miR-19b or miR-92a and the 3'UTR of DKK3 was validated using luciferase reporter assays. In conclusion, this study demonstrates that the MYCN-induced downregulation of DKK3 results from direct upregulation of miR-17-92 components effecting both DKK3 mRNA stability and translation which further contributes to the pleiotropic oncogenic effect of elevated MYCN levels. The strict MYCN-mediated regulation of DKK3 is suggestive for an important downstream function of the MYCN protein and thus warrants further investigations to unravel the role of DKK3 in NB.},
  author       = {De Brouwer, Sara and Mestdagh, Pieter and Lambertz, Irina and Pattyn, Filip and De Paepe, Anne and Westermann, Frank and Schroeder, Christina and Schulte, Johannes H and Schramm, Alexander and De Preter, Katleen and Vandesompele, Jo and Speleman, Franki},
  issn         = {0020-7136},
  journal      = {INTERNATIONAL JOURNAL OF CANCER},
  keyword      = {dickkopf-3,neuroblastoma,miR-17-92 cluster,N-MYC,RNA INTERFERENCE,PROSTATE-CANCER,DOWN-REGULATION,BETA-CATENIN,CELL-CYCLE,EXPRESSION,GENE,REIC/DKK-3,TARGET},
  language     = {eng},
  number       = {11},
  pages        = {2591--2598},
  title        = {Dickkopf-3 is regulated by the MYCN-induced miR-17-92 cluster in neuroblastoma},
  url          = {http://dx.doi.org/10.1002/ijc.26295},
  volume       = {130},
  year         = {2012},
}

Chicago
De Brouwer, Sara, Pieter Mestdagh, Irina Lambertz, Filip Pattyn, Anne De Paepe, Frank Westermann, Christina Schroeder, et al. 2012. “Dickkopf-3 Is Regulated by the MYCN-induced miR-17-92 Cluster in Neuroblastoma.” International Journal of Cancer 130 (11): 2591–2598.
APA
De Brouwer, S., Mestdagh, P., Lambertz, I., Pattyn, F., De Paepe, A., Westermann, F., Schroeder, C., et al. (2012). Dickkopf-3 is regulated by the MYCN-induced miR-17-92 cluster in neuroblastoma. INTERNATIONAL JOURNAL OF CANCER, 130(11), 2591–2598.
Vancouver
1.
De Brouwer S, Mestdagh P, Lambertz I, Pattyn F, De Paepe A, Westermann F, et al. Dickkopf-3 is regulated by the MYCN-induced miR-17-92 cluster in neuroblastoma. INTERNATIONAL JOURNAL OF CANCER. 2012;130(11):2591–8.
MLA
De Brouwer, Sara, Pieter Mestdagh, Irina Lambertz, et al. “Dickkopf-3 Is Regulated by the MYCN-induced miR-17-92 Cluster in Neuroblastoma.” INTERNATIONAL JOURNAL OF CANCER 130.11 (2012): 2591–2598. Print.