基因组和表观基因组调控的综合分析揭示了低级别胶质瘤中miRNA介导的肿瘤异质性和免疫逃避-动脉网

Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma

Nature 等信源发布 2024-07-06 04:14

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AbstractThe expression dysregulation of microRNAs (miRNA) has been widely reported during cancer development, however, the underling mechanism remains largely unanswered. In the present work, we performed a systematic integrative study for genome-wide DNA methylation, copy number variation and miRNA expression data to identify mechanisms underlying miRNA dysregulation in lower grade glioma.

摘要在癌症发展过程中，microRNA（miRNA）的表达失调已被广泛报道，然而，底层机制在很大程度上仍未得到解答。在目前的工作中，我们对全基因组DNA甲基化，拷贝数变异和miRNA表达数据进行了系统的综合研究，以确定低级别胶质瘤中miRNA失调的潜在机制。

We identify 719 miRNAs whose expression was associated with alterations of copy number variation or promoter methylation. Integrative multi-omics analysis revealed four subtypes with differing prognoses. These glioma subtypes exhibited distinct immune-related characteristics as well as clinical and genetic features.

我们鉴定了719个miRNA，其表达与拷贝数变异或启动子甲基化的改变有关。。这些神经胶质瘤亚型表现出独特的免疫相关特征以及临床和遗传特征。

By construction of a miRNA regulatory network, we identified candidate miRNAs associated with immune evasion and response to immunotherapy. Finally, eight prognosis related miRNAs were validated to promote cell migration, invasion and proliferation through in vitro experiments. Our study reveals the crosstalk among DNA methylation, copy number variation and miRNA expression for immune regulation in glioma, and could have important implications for patient stratification and development of biomarkers for immunotherapy approaches..

通过构建miRNA调控网络，我们确定了与免疫逃避和免疫治疗反应相关的候选miRNA。最后，通过体外实验验证了八种与预后相关的miRNA促进细胞迁移，侵袭和增殖。我们的研究揭示了DNA甲基化，拷贝数变异和miRNA表达在神经胶质瘤免疫调节中的相互作用，可能对患者分层和免疫治疗方法生物标志物的开发具有重要意义。。

IntroductionLower grade glioma (LGG) is the most common and aggressive central nervous system (CNS) tumor, which accounting for about 40% of all brain malignancies1. Most LGGs can be further classified according to specific type of cell with which they share histological features or molecular biomarkers, such as isocitrate dehydrogenase (IDH) mutation or O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation2,3.

引言低级别胶质瘤（LGG）是最常见和最具侵袭性的中枢神经系统（CNS）肿瘤，约占所有脑恶性肿瘤的40%1。大多数LGG可以根据它们具有组织学特征或分子生物标志物的特定细胞类型进一步分类，例如异柠檬酸脱氢酶（IDH）突变或O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）启动子甲基化2,3。

Despite tremendous progress has been made over the past decades for its early detection, surgical paradigm and multidisciplinary treatment, such as neoadjuvant chemotherapy and radiotherapy, the postoperative overall survival of LGG patients remains extremely low, particularly for high-grade glioma with worse prognoses for their malignant aggressivity4.

尽管在过去几十年中，LGG患者的早期发现，手术模式和多学科治疗（如新辅助化疗和放疗）取得了巨大进展，但LGG患者的术后总生存率仍然极低，特别是对于预后较差的高级别胶质瘤恶性侵袭性4。

In general, the prognosis of patients with glioma varies dramatically, which is dependent on different tumor grade, key gene alternation status, tumor microenvironment, and combination of different efficacious methods5. Recent genomic studies have brought a comprehensive view of glioma based on molecular profiling and identified different subtypes within the glioma that appear to correlate with disease etiology and therapy response6.

一般来说，胶质瘤患者的预后差异很大，这取决于不同的肿瘤分级，关键基因交替状态，肿瘤微环境以及不同有效方法的组合5。最近的基因组研究基于分子谱分析对胶质瘤进行了全面的研究，并确定了胶质瘤中不同的亚型，这些亚型似乎与疾病病因和治疗反应相关6。

Hence, there is an urgent need to characterize more specific and precise molecular signatures of LGG for its accurate diagnosis, individualized treatment and the prognosis assessment.MicroRNAs (miRNAs) are ~22 nt small non-coding RNAs that play an important role in post-transcriptional regulation, which precisely adjust the gene expression level by targeting mRNAs for its degradation or translational repression7,8.

因此，迫切需要表征LGG更具体，更精确的分子特征，以准确诊断，个体化治疗和预后评估。微小RNA（miRNA）是〜22 nt小的非编码RNA，在转录后调控中发挥重要作用，通过靶向mRNA降解或翻译抑制来精确调节基因表达水平7,8。

miRNAs are critical for normal development of organisms and are involved in a variety of biological processes including cell cycle, cell proliferation, differe.

。

Data availability

数据可用性

Data analyzed in this manuscript are already publicly available from The Cancer Genome Atlas (TCGA) data portal: https://portal.gdc.cancer.gov/ and the Chinese Glioma Genome Atlas (CGGA) data portal: http://www.cgga.org.cn/. The Count matrix of single cell RNA-seq data was obtained from the GEO database with the accession number GSE152273.

https://portal.gdc.cancer.gov/和中国胶质瘤基因组图谱（CGGA）数据门户：http://www.cgga.org.cn/.单细胞RNA-seq数据的计数矩阵是从GEO数据库获得的，登录号为GSE152273。

The source data behind the graphs in the paper are provided in Figshare at: https://doi.org/10.6084/m9.figshare.25989109.v197..

本文中图表背后的源数据在Figshare中提供，网址为：https://doi.org/10.6084/m9.figshare.25989109.v197..

Code availability

代码可用性

In this study, we used software general workflow codes, without generating any new code. R packages and specific functions, as well as softwares used are described in relevant sections in the “Method” section.

在这项研究中，我们使用软件通用工作流代码，而不生成任何新代码。R软件包和特定功能以及使用的软件在“方法”部分的相关章节中进行了描述。

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Yang, Z. Source data—Integrative analysis of genomic and epigenomic regulation reveals microRNA mediated tumor heterogeneity and immune evasion in lower grade glioma. figshare https://doi.org/10.6084/m9.figshare.25989109.v1 (2024).Download referencesAcknowledgementsThe study was supported by the National Natural Science Foundation of China (91959106, 32071270, 82072370, 82103376); Outstanding Innovative Research Team for Molecular Enzymology and Detection in Anhui Provincial Universities (2022AH010012); Program for Excellent Sci-tech Innovation Teams of Universities in Anhui Province (2022AH010074); the Major Science and Technology Projects in Anhui Province (202003a06020009); Anhui Natural Science Foundation (2208085MC48); Key University Science Research Project of Anhui Province (2023AH051746, 2023AH051768); Climbing Peak Training Program for Innovative Technology team of Yijishan Hospital, Wannan Medical College (PF201904); Peak Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College (GF2019T01, GF2019G15); the Open Project of Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College (RNA202205); Science and Technology Application Basic Research Project of Wuhu (2022jc60); and Key Research and Development Foundation supported by Science and Technology Department of Sichuan Province (2023YFS0243).

Yang，Z。来源数据基因组和表观基因组调控的综合分析揭示了低级别胶质瘤中microRNA介导的肿瘤异质性和免疫逃避。figshare公司https://doi.org/10.6084/m9.figshare.25989109.v1（2024年）。下载参考文献致谢该研究得到了国家自然科学基金（91959106320712708207082103376）的支持；安徽省属高校分子酶学与检测优秀创新研究团队（2022AH010012）；安徽省高校优秀科技创新团队计划（2022AH010074）；安徽省重大科技项目（202003a06020009）；安徽省自然科学基金（2208085MC48）；安徽省重点大学科研项目（2023AH0517462023AH051768）；皖南医学院弋矶山医院创新技术团队攀登高峰培训计划（PF201904）；皖南医学院弋矶山医院科研高峰培训计划（GF2019T01，GF2019G15）；皖南医学院安徽高校非编码RNA转化研究重点实验室开放项目（RNA202205）；芜湖市科技应用基础研究项目（2022jc60）；四川省科学技术厅重点研究发展基金（2023YFS0243）。

The sponsors have no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.Author informationAuthor notesThese authors contributed equally: Zhen Yang, Xiaocen Liu, Hao Xu.Authors and AffiliationsCenter for Medical Research and Innovation of Pudong Hospital, an.

赞助商在研究设计，数据的收集，分析和解释，报告的撰写以及提交文章发表的决定中没有任何作用。作者信息作者注意到这些作者做出了同样的贡献：甄阳，刘晓岑，徐浩。浦东医院医学研究与创新的作者和附属机构。

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PubMed Google ScholarContributionsZ.Y., K.L. and H.Y. conceived the study. X.L. and H.X. performed experimental validation analysis. A.E.T. supervised data analysis. L.X. and JY.L. performed data analysis. M.F., JU.L., H.Z., Y.W., L.Z. and Y.H. collected and processed samples.

PubMed谷歌学术贡献。Y、，K.L.和H.Y.构思了这项研究。十、 L.和H.X.进行了实验验证分析。A、 E.T.监督数据分析。五十、 X.和JY。五十、进行了数据分析。M、 F.，朱。五十、，H.Z.，Y.W.，L.Z.和Y.H.收集并处理了样品。

Z.Y. wrote the paper. A.E.T. revised the paper. All authors read and approved the paper.Corresponding authorsCorrespondence to.

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Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Christina Karlsson Rosenthal. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleYang, Z., Liu, X., Xu, H. et al. Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma.

转载和许可本文引用本文Yang，Z.，Liu，X.，Xu，H。等人。基因组和表观基因组调控的综合分析揭示了miRNA介导的低级别胶质瘤的肿瘤异质性和免疫逃避。

Commun Biol 7, 824 (2024). https://doi.org/10.1038/s42003-024-06488-9Download citationReceived: 12 March 2024Accepted: 21 June 2024Published: 06 July 2024DOI: https://doi.org/10.1038/s42003-024-06488-9Share 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.

Commun Biol 7824（2024）。https://doi.org/10.1038/s42003-024-06488-9Download引文接收日期：2024年3月12日接受日期：2024年6月21日发布日期：2024年7月6日OI：https://doi.org/10.1038/s42003-024-06488-9Share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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