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Journal ArticleDOI

The MicroRNA Landscape of MYCN-Amplified Neuroblastoma.

07 May 2021-Frontiers in Oncology (Frontiers Media SA)-Vol. 11, pp 647737-647737
TL;DR: In this paper, the miRNome of 97 neuroblastoma-derived cells was analyzed using microRNA trapping by RNA affinity purification to reveal the MYCN-dependent miRNOME.
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.

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Citations
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Journal ArticleDOI
29 Oct 2021-Diseases
TL;DR: In this article, the role of BHLH Transcription factor (myCN) in neuroblastoma has been investigated from all possible mechanistic sites, including the references of myCN in the literature, the gene's anatomy along with its transcripts, the protein's anatomy, the epigenetic mechanisms regulating MYCN expression and function, as well as MYCN amplification.
Abstract: MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) has been one of the most studied genes in neuroblastoma. It is known for its oncogenetic mechanisms, as well as its role in the prognosis of the disease and it is considered one of the prominent targets for neuroblastoma therapy. In the present work, we attempted to review the literature, on the relation between MYCN and neuroblastoma from all possible mechanistic sites. We have searched the literature for the role of MYCN in neuroblastoma based on the following topics: the references of MYCN in the literature, the gene’s anatomy, along with its transcripts, the protein’s anatomy, the epigenetic mechanisms regulating MYCN expression and function, as well as MYCN amplification. MYCN plays a significant role in neuroblastoma biology. Its functions and properties range from the forming of G-quadraplexes, to the interaction with miRNAs, as well as the regulation of gene methylation and histone acetylation and deacetylation. Although MYCN is one of the most primary genes studied in neuroblastoma, there is still a lot to be learned. Our knowledge on the exact mechanisms of MYCN amplification, etiology and potential interventions is still limited. The knowledge on the molecular mechanisms of MYCN in neuroblastoma, could have potential prognostic and therapeutic advantages.

9 citations

Journal ArticleDOI
TL;DR: In this paper , the role of micro RNAs in anti-tumor immune response via a range of data-driven workflows and in vitro & in vivo experiments was explored.

7 citations

Journal ArticleDOI
16 Sep 2021-Cancers
TL;DR: In this article, the authors focus on the role of YAP in neuroblastoma and further describe its demonstrated and potential effects on the solid tumor microenvironment (TME) and discuss the therapeutic strategies for inhibiting YAP.
Abstract: Neuroblastoma is the most common extra-cranial pediatric solid tumor that accounts for more than 15% of childhood cancer-related deaths. High risk neuroblastomas that recur during or after intense multimodal therapy have a <5% chance at a second sustained remission or cure. The solid tumor microenvironment (TME) has been increasingly recognized to play a critical role in cancer progression and resistance to therapy, including in neuroblastoma. The Yes-Associated Protein (YAP) in the Hippo pathway can regulate cancer proliferation, tumor initiation, and therapy response in many cancer types and as such, its role in the TME has gained interest. In this review, we focus on YAP and its role in neuroblastoma and further describe its demonstrated and potential effects on the neuroblastoma TME. We also discuss the therapeutic strategies for inhibiting YAP in neuroblastoma.

3 citations

Journal ArticleDOI
01 Sep 2022-Cancers
TL;DR: The aim of this review is to describe the current knowledge in the diagnosis, prognosis and therapeutic approaches of HR-NB, particularly in relation to MYCN, to highlight how MYCN influences the HR- NB scenario and the new therapeutic approaches that are currently proposed to target it.
Abstract: Simple Summary Neuroblastoma is one of the most diffuse and the deadliest cancer in children. While many advances have been made in the last few decades to improve patients’ outcome, high-risk neuroblastoma (HR-NB) still shows a very aggressive pattern of development and poor prognosis, with only a 50% chance of 5-year survival. Moreover, while many factors contribute to defining the high-risk condition, MYCN status is well established as the major element in pathology disclosure. The aim of this review is to describe the current knowledge in the diagnosis, prognosis and therapeutic approaches of HR-NB, particularly in relation to MYCN. The review highlights how MYCN influences the HR-NB scenario and the new therapeutic approaches that are currently proposed to target it, in consideration of MYCN as a highly relevant target for HR-NB patient management. Abstract Among childhood cancers, neuroblastoma is the most diffuse solid tumor and the deadliest in children. While to date, the pathology has become progressively manageable with a significant increase in 5-year survival for its less aggressive form, high-risk neuroblastoma (HR-NB) remains a major issue with poor outcome and little survivability of patients. The staging system has also been improved to better fit patient needs and to administer therapies in a more focused manner in consideration of pathology features. New and improved therapies have been developed; nevertheless, low efficacy and high toxicity remain a staple feature of current high-risk neuroblastoma treatment. For this reason, more specific procedures are required, and new therapeutic targets are also needed for a precise medicine approach. In this scenario, MYCN is certainly one of the most interesting targets. Indeed, MYCN is one of the most relevant hallmarks of HR-NB, and many studies has been carried out in recent years to discover potent and specific inhibitors to block its activities and any related oncogenic function. N-Myc protein has been considered an undruggable target for a long time. Thus, many new indirect and direct approaches have been discovered and preclinically evaluated for the interaction with MYCN and its pathways; a few of the most promising approaches are nearing clinical application for the investigation in HR-NB.

2 citations

Journal ArticleDOI
TL;DR: In this article , a druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1 was investigated.
Abstract: Abstract Background Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1 , and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment. Methods Candidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models. Results We reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho-adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1-driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also. Conclusion We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.

1 citations

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