The MicroRNA Landscape of MYCN-Amplified Neuroblastoma.

Danny Misiak,Stefan Hüttelmaier,Johannes H Schulte,Nadine Bley,Jessica L Bell,Marcell Lederer,Bianca Busch,Sven Hagemann

doi:10.3389/fonc.2021.647737

Abstract

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.

Highlights

Neuroblastoma, the most common extracranial solid childhood tumor, originates from precursors of the sympathetic nervous system and account for approximately 15% of all cancer-related death in infants [1]
These studies reveal that MYCN-amplified (MNA) neuroblastoma is sharply distinguished by the upregulated expression of miRNAs associated with adverse diseases outcome and the downregulation of miRNAs associated with more favorable prognosis
Together with ample evidence for a pivotal role of the miR-17-92 cluster miRNAs in controlling MYCN expression, this indicates that this miRNA family is an essential regulator of MYCN mRNA abundance

Summary

Introduction

Neuroblastoma, the most common extracranial solid childhood tumor, originates from precursors of the sympathetic nervous system and account for approximately 15% of all cancer-related death in infants [1]. The clinical presentation of neuroblastoma is remarkably heterogeneous in pathological, genetic and biological characteristics, ranging from spontaneous regression or differentiation of the tumor to a high-risk aggressive disease. Neuroblastoma is thought to arise from sympathoadrenal lineage precursor cells, derived from the neural crest. Risk classification depends on several clinical and biological factors, such as age at diagnosis, stage, histology and genetic aberrations [2]. The clinical outcome of patients with high-risk neuroblastoma stagnates despite many therapeutic approaches like surgery, radiation, chemotherapy, stem cell transplantation or immunotherapy [2]. The 5-year survival rate of high-risk patients is still under 50% and the treatment remains challenging [3]

Methods

Results

Conclusion