IL-33调控肿瘤免疫微环境中IFN-γ的生物信息学分析

doi:10.3969/j.issn.1006-7795.2021.02.014

摘要/Abstract

摘要： 目的通过生物信息学方法分析白细胞介素-33(interleukin-33,IL-33)对肿瘤免疫微环境的影响,探讨在肿瘤免疫微环境中IL-33上调干扰素-γ(interferon-gamma, IFN-γ)表达的机制。方法应用生存曲线在线分析工具分析IL-33表达对患者生存时间的影响。从基因表达综合数据库(gene expression omnibus,GEO)中下载数据,进行基因本体论(gene ontology,GO)分析、京都基因和基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析和蛋白网络相互作用分析,探讨IL-33对相关基因的功能和信号通路的影响。从临床蛋白质组肿瘤分析协会(Clinical Proteomic Tumor Analysis Consortium, CPTAC)蛋白和蛋白磷酸化组数据库中下载数据,分析IL-33表达与异质性胞核核糖核蛋白D(heterogeneous nuclear ribonucleoprotein D,HNRNPD或AU-rich element binding factor 1,AUF1)表达的相关性。结果生存曲线在线分析结果显示IL-33的高表达显著改善多种癌症生存预后。在IL-33受体St2敲除鼠结肠癌模型中,IFN-γ表达显著下调。IL-33影响的基因主要富集于对IFN-γ的反应,对IFN-β的反应,固有免疫调控等信号通路和生物过程中。CPTAC蛋白质组数据分析提示IL-33和AUF1表达显著负相关(r=-0.64,P<0.001)。结论 IL-33在肿瘤免疫微环境中可以增强免疫细胞IFN-γ的表达,IL-33可以通过下调AUF1的表达,阻止AUF1所属的“AUF1和信号转导调控复合体”对IFN-γ mRNA的攻击。

关键词: 白细胞介素-33, 计算生物学, 免疫疗法, 转录组, 蛋白质组

Abstract: Objective To analyze the impact of interleukin-33 (IL-33) on tumor microenvironment by bioinformatic methods. To find the mechanism by which IL-33 upregulates interferon-gamma (IFN-γ) expression.Methods We analyzed the impact of IL-33 expression on patients' survival time by the Kaplan Meier Online analyzing tool. Data were downloaded from gene expression omnibus (GEO), which were subject to a gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We found the function and signal pathway of genes influenced by IL-33 and downloaded data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) from which we extracted the expression of IL-33 and AU-rich element binding factor 1 (AUF1) and analyzed the correlation between IL-33 and AUF1. Results Kaplan Meier Online analysis results showed that patients who expressed IL-33 at high level had a better prognosis. In the St2 (the receptor of IL-33) knockout mouse colon carcinoma model, the expression of IFN-γ significantly decreased. The genes influenced by IL-33 were mainly annotated by genes respond to interferon-gamma, genes of cellular response to interferon-gamma, genes responding to virus, genes regulating response to biotic stimulus. The data from CPTAC revealed that the expression of IL-33 and AUF1 had a significant negative correlation. Conclusion IL-33 can upregulate the expression of IFN-γ of immune cells in tumor microenvironment. IL-33 could downregulate the expression of AUF1, which belongs to AUF1- and signal transduction-regulated complex (ASTRC). AUF1 attacked mRNA whose 3'UTR have an AU-rich element (ARE). IL-33 could protect IFN-γ mRNA by downregulating AUF1.

Key words: interleukin-33, computational biology, immunotherapy, transcriptome, proteome

中图分类号:

R392.12

韩鸿举, 苏子阳, 周玉洁, 王玺. IL-33调控肿瘤免疫微环境中IFN-γ的生物信息学分析[J]. 首都医科大学学报, 2021, 42(2): 243-250.

Han Hongju, Su Ziyang, Zhou Yujie, Wang Xi. Bioinformatic analysis of the influence of IL-33 on IFN-γ expression in tumor microenvironment[J]. Journal of Capital Medical University, 2021, 42(2): 243-250.

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