MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors.
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.
Mestdagh
P
P
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Fredlund
E
E
Pattyn
F
F
Schulte
J H
JH
Muth
D
D
Vermeulen
J
J
Kumps
C
C
Schlierf
S
S
De Preter
K
K
Van Roy
N
N
Noguera
R
R
Laureys
G
G
Schramm
A
A
Eggert
A
A
Westermann
F
F
Speleman
F
F
Vandesompele
J
J
D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000187:drug effects* / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000494:pharmacology*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000628:therapy; D009687:Nuclear Proteins / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology; D016896:Treatment Outcome
C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors