全面描绘肿瘤微环境和 m6A RNA 甲基化调控因子,并研究其对宫颈癌 PD-L1 和免疫浸润的影响。

Comprehensive characterization of tumor microenvironment and m6A RNA methylation regulators and its effects on PD-L1 and immune infiltrates in cervical cancer.

机构信息

Center of Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

出版信息

Front Immunol. 2022 Aug 26;13:976107. doi: 10.3389/fimmu.2022.976107. eCollection 2022.

Abstract

Understanding the role of N6-adenosine methylation (m6A) in the tumor microenvironment (TME) is important since it can contribute to tumor development. However, the research investigating the association between m6A and TME and cervical cancer is still in its early stages. The aim of this study was to discover the possible relationship between m6A RNA methylation regulators, TME, PD-L1 expression levels, and immune infiltration in cervical cancer. We gathered RNA-seq transcriptome data and clinical information from cervical cancer patients using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. To begin, researchers assessed the differences in m6A regulatory factor expression levels between cervical cancer and normal tissues. Clustering analysis was adapted to assess PD-L1 expression, immunological score, immune cell infiltration, TME, and probable pathways in cervical cancer samples. The majority of m6A regulators were found to be considerably overexpressed in cervical cancer tissues. Using consensus clustering of 21 m6A regulators, we identified two subtypes (clusters 1/2) of cervical cancer, and we found that WHO stage and grade were associated with the subtypes. PD-L1 expression increased dramatically in cervical cancer tissues and was significantly linked to ALKBH5, FTO, METTL3, RBM15B, YTHDF1, YTHDF3, and ZC3H13 expression levels. Plasma cells and regulatory T cells (Tregs) were considerably elevated in cluster 2. Cluster 1 is involved in numerous signature pathways, including basal transcription factors, cell cycle, RNA degradation, and the spliceosome. The prognostic signature-based riskscore (METTL16, YTHDF1, and ZC3H13) was found to be an independent prognostic indicator of cervical cancer. The tumor immune microenvironment (TIME) was linked to m6A methylation regulators, and changes in their copy number will affect the quantity of tumor-infiltrating immune cells dynamically. Overall, our research discovered a powerful predictive signature based on m6A RNA methylation regulators. This signature correctly predicted the prognosis of cervical cancer patients. The m6A methylation regulator could be a critical mediator of PD-L1 expression and immune cell infiltration, and it could have a significant impact on the TIME of cervical cancer.

摘要

了解 N6-腺嘌呤甲基化 (m6A) 在肿瘤微环境 (TME) 中的作用很重要,因为它可能有助于肿瘤的发展。然而,关于 m6A 与 TME 和宫颈癌之间的关联的研究仍处于早期阶段。本研究的目的是发现 m6A RNA 甲基化调节剂、TME、PD-L1 表达水平和宫颈癌免疫浸润之间可能存在的关系。我们使用癌症基因组图谱 (TCGA) 和基因型组织表达 (GTEx) 数据库从宫颈癌患者中收集 RNA-seq 转录组数据和临床信息。研究人员首先评估了 m6A 调节因子在宫颈癌和正常组织中的表达水平差异。聚类分析用于评估宫颈癌样本中的 PD-L1 表达、免疫评分、免疫细胞浸润、TME 和可能的途径。大多数 m6A 调节剂在宫颈癌组织中被发现表达显著上调。使用 21 个 m6A 调节剂的共识聚类,我们鉴定出两种宫颈癌亚型(簇 1/2),并且发现 WHO 分期和分级与亚型相关。PD-L1 表达在宫颈癌组织中显著升高,与 ALKBH5、FTO、METTL3、RBM15B、YTHDF1、YTHDF3 和 ZC3H13 的表达水平显著相关。在簇 2 中,浆细胞和调节性 T 细胞 (Treg) 显著升高。簇 1 参与了许多特征性途径,包括基础转录因子、细胞周期、RNA 降解和剪接体。基于预后特征的风险评分 (METTL16、YTHDF1 和 ZC3H13) 被发现是宫颈癌的独立预后指标。肿瘤免疫微环境 (TIME) 与 m6A 甲基化调节剂相关,其拷贝数的变化将动态影响肿瘤浸润免疫细胞的数量。总的来说,我们的研究发现了一个基于 m6A RNA 甲基化调节剂的强大预测特征。该特征可以正确预测宫颈癌患者的预后。m6A 甲基化调节剂可能是 PD-L1 表达和免疫细胞浸润的关键调节剂,可能对宫颈癌的 TIME 产生重大影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4c4/9458859/e6314d296fb8/fimmu-13-976107-g001.jpg

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