期刊
ONCOTARGET
卷 6, 期 7, 页码 5204-5216出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2477
关键词
MYCN; microRNA; neuroblastoma; feedback regulation; cross-species
资金
- GOA [01G01910]
- European Union
- Belgian Foundation against Cancer (Stichting Tegen Kanker) [SCIE 2010-177]
- Fund for Scientific Research Flanders (FWO) [G.0530.12N]
- Agency for Innovation by Science and Technology (IWT) [IWT 101506]
- Flemish League against Cancer (Vlaamse Liga tegen Kanker)
- Ghent University [BOF 01D35609]
- FWO
- NHMRC Australia
- Cancer Institute NSW
- Cancer Council NSW
MYCN is a transcription factor that plays key roles in both normal development and cancer. In neuroblastoma, MYCN acts as a major oncogenic driver through pleiotropic effects controlled by multiple protein encoding genes as well as microRNAs (miRNAs). MYCN activity is tightly regulated at the level of transcription and protein stability through various mechanisms. Like most genes, MYCN is further controlled by miRNAs, but the full complement of all miRNAs implicated in this process has not been determined through an unbiased approach. To elucidate the role of miRNAs in regulation of MYCN, we thus explored the MYCN-miRNA interactome to establish miRNAs controlling MYCN expression levels. We combined results from an unbiased and genome-wide high-throughput miRNA target reporter screen with miRNA and mRNA expression data from patients and a murine neuroblastoma progression model. We identified 29 miRNAs targeting MYCN, of which 12 miRNAs are inversely correlated with MYCN expression or activity in neuroblastoma tumor tissue. The majority of MYCN-targeting miRNAs in neuroblastoma showed a decrease in expression during murine MYCN-driven neuroblastoma tumor development. Therefore, we provide evidence that MYCN-targeting miRNAs are preferentially downregulated in MYCN-driven neuroblastoma, suggesting that MYCN negatively controls the expression of these miRNAs, to safeguard its expression.
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