联合代谢组学和转录组学分析系统地揭示了MYCN对神经母细胞瘤的影响-动脉网

Joint metabolomics and transcriptomics analysis systematically reveal the impact of MYCN in neuroblastoma

Nature 等信源发布 2024-08-30 15:18

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AbstractThe limited understanding of the molecular mechanism underlying MYCN-amplified (MNA) neuroblastoma (NB) has hindered the identification of effective therapeutic targets for MNA NB, contributing to its higher mortality rate compared to MYCN non-amplified (non-MNA) NB. Therefore, a comprehensive analysis integrating metabolomics and transcriptomics was conducted to systematically investigate the MNA NB.

摘要对MYCN扩增（MNA）神经母细胞瘤（NB）的分子机制了解有限，阻碍了MNA NB有效治疗靶点的鉴定，导致其死亡率高于MYCN非扩增（非MNA）NB。因此，进行了整合代谢组学和转录组学的综合分析，以系统地研究MNA NB。

Metabolomics analysis utilized plasma samples from 28 MNA NB patients and 68 non-MNA NB patients, while transcriptomics analysis employed tissue samples from 15 MNA NB patients and 37 non-MNA NB patients. Notably, joint metabolomics and transcriptomics analysis was performed. A total of 46 metabolites exhibited alterations, with 21 displaying elevated levels and 25 demonstrating reduced levels in MNA NB.

代谢组学分析使用了28名MNA NB患者和68名非MNA NB患者的血浆样本，而转录组学分析使用了15名MNA NB患者和37名非MNA NB患者的组织样本。值得注意的是，进行了联合代谢组学和转录组学分析。共有46种代谢物表现出改变，其中21种表现出升高的水平，25种表现出MNA NB水平降低。

In addition, 884 mRNAs in MNA NB showed significant changes, among which 766 mRNAs were higher and 118 mRNAs were lower. Joint-pathway analysis revealed three aberrant pathways involving glycerolipid metabolism, purine metabolism, and lysine degradation. This study highlights the substantial differences in metabolomics and transcriptomics between MNA NB and non-MNA NB, identifying three abnormal metabolic pathways that may serve as potential targets for understanding the molecular mechanisms underlying MNA NB..

此外，MNA NB中的884个mRNA显示出显着变化，其中766个mRNA较高，118个mRNA较低。联合途径分析揭示了三种异常途径，涉及甘油脂质代谢，嘌呤代谢和赖氨酸降解。这项研究强调了MNA-NB和非MNA-NB在代谢组学和转录组学方面的实质性差异，确定了三种异常代谢途径，这些途径可能是理解MNA-NB潜在分子机制的潜在靶标。。

IntroductionNeuroblastoma (NB) is a malignancy of the peripheral nervous system that arises from the embryonic neural crest, characterized by an insidious onset and rapid progression. NB constitutes 8% of all pediatric cancer cases, while accounting for 15% of childhood1,2,3. The clinical manifestations of NB exhibit significant heterogeneity, ranging from spontaneous regression or differentiation with an overall survival rate of 85–90%, to refractory and metastatic tumors, wherein less than 50% of patients survive even after intensive therapy4.

简介神经母细胞瘤（NB）是由胚胎神经嵴引起的周围神经系统恶性肿瘤，其特征是起病隐匿且进展迅速。NB占所有儿科癌症病例的8%，而占儿童期的15%1,2,3。NB的临床表现表现出显着的异质性，从自发消退或分化，总生存率为85-90%，到难治性和转移性肿瘤，即使经过强化治疗，仍有不到50%的患者存活4。

One of the factors contributing to NB heterogeneity is MYCN amplification (MNA), which has been shown to promote NB growth and progression, and correlate with treatment resistance and unfavorable prognosis in NB5. For instance, in comparison to MNA NB, MYCN non-amplified (non-MNA) NB patients had higher event free survival (EFS) and overall survival (OS) (EFS and OS: 82.5% and 90.8% versus 36.9% and 44.8%), indicating that MNA has a tremendous impact on the prognosis of NB6.

导致NB异质性的因素之一是MYCN扩增（MNA），已被证明可促进NB的生长和进展，并与NB5的治疗耐药性和不良预后相关。例如，与MNA NB相比，MYCN非扩增（非MNA）NB患者的无事件生存率（EFS）和总生存率（OS）更高（EFS和OS:82.5%和90.8%，而36.9%和44.8%），表明MNA对NB6的预后有巨大影响。

Furthermore, the prevalence of MNA in NB patients is 20–30%, whereas MNA is detected in about 50% of high risk NB (HR-NB) cases with an overall survival rate of less than 50%7,8. Studies have also shown that MYCN, as a major transcription factor, is important for normal cell proliferation and apoptosis.

此外，NB患者中MNA的患病率为20-30%，而在约50%的高危NB（HR-NB）病例中检测到MNA，总生存率低于50%7,8。研究还表明，MYCN作为一种主要的转录因子，对正常的细胞增殖和凋亡很重要。

MNA may lead to inhibition of apoptosis signals and continuous proliferation, which may eventually lead to the development of NB9. Nevertheless, there is a dearth of studies that explicitly elucidate the molecular mechanism underlying MNA in NB or its associated therapeutic targets, thereby contributing to the elevated mortality observed in MNA NB compared to non-MNA NB10.

MNA可能导致细胞凋亡信号的抑制和持续增殖，最终可能导致NB9的发展。然而，缺乏明确阐明NB中MNA或其相关治疗靶点的分子机制的研究，从而导致MNA NB中观察到的死亡率高于非MNA NB10。

Therefore, it is imperative to investigate the aberrant pathway of MNA NB in order to e.

因此，必须研究MNA-NB的异常途径，以便e。

Data availability

数据可用性

We have submitted the raw RNA-seq data to NCBI (https://www.ncbi.nlm.nih.gov/sra) under the accession number PRJNA884866. Besides, we have uploaded mass spectrometry data to the MetaboLights (https://www.ebi.ac.uk/metabolights/) with the number of MTBLS6352.

我们已经向NCBI提交了原始RNA-seq数据(https://www.ncbi.nlm.nih.gov/sra)登记号为PRJNA884866。此外，我们已经将质谱数据上传到代谢仪(https://www.ebi.ac.uk/metabolights/)编号为MTBLS6352。

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Download referencesAcknowledgementsThe authors sincerely thank all participants for participating in this study, as this study would not be possible without their valuable contributions.FundingThis work were funded by National Natural Science Foundation of China (32201237), Scientific and technological projects of Henan province (222102310270, 222102310109, 232102311135), Henan medical science and technology program (LHGJ20220767), Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease foundation (EKB202204).Author informationAuthors and AffiliationsHealth Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, ChinaBang Du, Pin Zhang, Mengxin Zhang, Zhidan Yu, Lifeng Li, Xianwei Zhang & Wancun ZhangThe First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, Luoyang, 471003, ChinaYingyu ZhangHenan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, ChinaLigong Hou & Wancun ZhangHenan Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, ChinaQionglin Wang & Wancun ZhangAuthorsBang DuView author publicationsYou can also search for this author in.

下载参考文献致谢作者衷心感谢所有参与者参与这项研究，因为如果没有他们的宝贵贡献，这项研究是不可能的。资助这项工作由国家自然科学基金（32201237），河南省科技项目（22210210270222102310923211135），河南省医学科学技术计划（LHGJ20220767），河南省儿科疾病防治国际联合实验室基金（EKB202204）资助。作者信息作者及所属单位郑州大学附属儿童医院河南省儿科肿瘤精确诊断与治疗重点实验室，郑州，450018，杜邦邦，张斌，张梦欣，于志丹，李立峰，张贤伟，张万村河南科技大学临床医学院第一附属医院，河南省罕见病重点实验室，内分泌与代谢中心，洛阳，471003，中国张颖玉河南省儿童疾病预防与治疗国际联合实验室，郑州大学附属儿童医院，郑州，450018，中国李公侯和张万村河南省儿童遗传与代谢重点实验室疾病，郑州大学附属儿童医院，郑州，450018，中国王琼林和张万村作者Bang DuView作者出版物您也可以在中搜索该作者。

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PubMed Google ScholarContributionsThe manuscript was written by B. D.; Y. Z. and P. Z. collected the data; M. Z., Z. Y., L. L. and L. H. analyzed the data; Q. W. organized the charts. X. Z. were responsible for the experimental design, while W. Z. oversaw the overall study. All authors critically reviewed the manuscript.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献手稿由B.D.撰写。；Y、；M、 Z.，Z.Y.，L.L.和L.H.分析了数据；Q、 W.整理图表。十、 Z.负责实验设计，而W.Z.负责整个研究。所有作者都严格审查了手稿。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleDu, B., Zhang, Y., Zhang, P. et al. Joint metabolomics and transcriptomics analysis systematically reveal the impact of MYCN in neuroblastoma.

转载和许可本文引用本文Du，B.，Zhang，Y.，Zhang，P。等人。联合代谢组学和转录组学分析系统地揭示了MYCN在神经母细胞瘤中的影响。

Sci Rep 14, 20155 (2024). https://doi.org/10.1038/s41598-024-71211-xDownload citationReceived: 08 January 2024Accepted: 26 August 2024Published: 30 August 2024DOI: https://doi.org/10.1038/s41598-024-71211-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1420155（2024）。https://doi.org/10.1038/s41598-024-71211-xDownload引文接收日期：2024年1月8日接受日期：2024年8月26日发布日期：2024年8月30日OI：https://doi.org/10.1038/s41598-024-71211-xShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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Keywords

关键词

MYCN amplificationNeuroblastomaMetabolomicsTranscriptomicsTherapeutic targetMolecular mechanism

MYCN扩增神经母细胞瘤代谢组学转录组学治疗靶点分子机制

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