MYCN gene amplification and upregulated expression are major hallmarks in the progression of high-risk
neuroblastoma. MYCN expression and function in modulating gene synthesis in
neuroblastoma is controlled at virtually every level, including poorly understood regulation at the post-transcriptional level. MYCN modulates the expression of various
microRNAs including the miR-17-92 cluster. MYCN
mRNA expression itself is subjected to the control by
miRNAs, most prominently the miR-17-92 cluster that balances MYCN expression by feed-back regulation. This homeostasis seems disturbed in
neuroblastoma where MYCN upregulation coincides with severely increased expression of the miR-17-92 cluster. In the presented study, we applied high-throughput next generation sequencing to unravel the miRNome in a cohort of 97
neuroblastomas, representing all clinical stages. Aiming to reveal the MYCN-dependent miRNome, we evaluate
miRNA expression in MYCN-amplified as well as none amplified
tumor samples. In correlation with survival data analysis of differentially expressed
miRNAs, we present various putative oncogenic as well as
tumor suppressive
miRNAs in
neuroblastoma. Using
microRNA trapping by
RNA affinity purification, we provide a comprehensive view of MYCN-regulatory
miRNAs in
neuroblastoma-derived cells, confirming a pivotal role of the miR-17-92 cluster and moderate association by the let-7
miRNA family. Attempting to decipher how MYCN expression escapes elevated expression of inhibitory
miRNAs, we present evidence that
RNA-binding proteins like the IGF2
mRNA binding protein 1 reduce
miRNA-directed downregulation of MYCN in
neuroblastoma. Our findings emphasize the potency of post-transcriptional regulation of MYCN in
neuroblastoma and unravel new avenues to pursue inhibition of this potent oncogene.