Abstract
Increased activity of MYC protein-family members is a common feature in many cancers. Using neuroblastoma as a tumor model, we established a microRNA (miRNA) signature for activated MYCN/c-MYC signaling in two independent primary neuroblastoma tumor cohorts and provide evidence that c-MYC and MYCN have overlapping functions. On the basis of an integrated approach including miRNA and messenger RNA (mRNA) gene expression data we show that miRNA activation contributes to widespread mRNA repression, both in c-MYC- and MYCN-activated tumors. c-MYC/MYCN-induced miRNA activation was shown to be dependent on c-MYC/MYCN promoter binding as evidenced by chromatin immunoprecipitation. Finally, we show that pathways, repressed through c-MYC/MYCN miRNA activation, are highly correlated to tumor aggressiveness and are conserved across different tumor entities suggesting that c-MYC/MYCN activate a core set of miRNAs for cooperative repression of common transcriptional programs related to disease aggressiveness. Our results uncover a widespread correlation between miRNA activation and c-MYC/MYCN-mediated coding gene expression modulation and further substantiate the overlapping functions of c-MYC and MYCN in the process of tumorigenesis.
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Acknowledgements
We acknowledge Q Wang and J Maris for providing the neuroblastoma microarray data set. This research was funded by the Gent University Research Fund (BOF 01D31406 to PM, BOF 01F07207 to FP, BOF 01Z09407 to J Vandesompele), the Fondation pour la recherche Nuovo-Soldati (J Vermeulen), RD06/0020/0102 from RTICC/ISCIII to RN, the Fund for Scientific Research (grant number: G.0198.08 and 31511809), the Belgian Kid's Fund and the Stichting tegen Kanker. KDP is a post-doctoral researcher with the Fund for Scientific Research-Flanders. We acknowledge the support of the European Community under the FP6 (project: STREP: EET-pipeline, number: 037260).
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Mestdagh, P., Fredlund, E., Pattyn, F. et al. MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors. Oncogene 29, 1394–1404 (2010). https://doi.org/10.1038/onc.2009.429
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DOI: https://doi.org/10.1038/onc.2009.429
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