Microarray analysis of the expression profile of immune-related gene in rapid recurrence early-stage lung adenocarcinoma
Microarray analysis of the expression profile of immune-related gene in rapid recurrence early-stage lung adenocarcinoma
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快速复发早期肺腺癌免疫相关基因表达谱的微阵列分析
DOI：
10.1007/s00432-020-03287-7
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发表时间：
2020-06-18
影响因子：
3.6
通讯作者：
Wang, Dong
中科院分区：
文献类型：
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作者：
Liu, Jie;Yang, Xiao;Wang, Dong
背景尽管早期肺腺癌（ES-LUAD）的诊断已取得很大进展，但快速复发的ES-LUAD患者的预后仍然较差。重要的是，目前还没有有效且精确的方法来筛查可能出现快速复发的患者。因此,有必要鉴定快速复发和非快速复发ES-LUAD患者中潜在的差异表达基因(DEG)。方法采用Affymetrix GeneChip人类转录组芯片鉴定快速复发和非快速复发ES-LUAD患者之间的DEG。快速复发定义为无复发生存期 (RFS) ≤ 1 年，非快速复发定义为 RFS ≥ 3 年。通过GO和KEGG通路富集分析分析DEG的生物学功能。已识别 DEG 的蛋白质-蛋白质相互作用 (PPI) 网络由 STRING 和 Cytoscape 软件进行。通过免疫组织化学(IHC)验证关键枢纽基因和肿瘤浸润淋巴细胞(TIL)的表达水平。结果在有和没有快速复发的ES-LUAD患者之间共鉴定出416个DEG。 GO分析结果显示，细胞成分领域前10个类别中有2个、分子功能领域前10个类别中有2个、生物过程领域前10个类别中有9个与免疫功能相关。 KEGG分析结果显示，排名前8的通路中有6条在功能上参与免疫调节和炎症反应。 PPI网络分析确定了10个关键的节点蛋白，包括EGFR、MMP9、IL-1β、PTGS2、MMP1和5个组蛋白，它们构成了25个关键相互作用。 IL-1β和PTGS2表达与免疫密切相关，IHC分析进一步揭示IL-1β和PTGS2的低表达与快速复发相关。 Kaplan-Meier 分析进一步显示，IL-1β 或 PTGS2 表达较低的 LUAD 患者 RFS 较差。当CD3+、CD4+、CD8+和CD20+亚群的TIL密度小于20%时，ES-LUAD患者快速复发的概率较高。结论快速复发患者与非快速复发患者免疫相关基因的表达存在显着差异。 IL-1β和PTGS2等免疫相关基因以及TIL密度（20%）在ES-LUAD的快速复发中发挥着重要作用。该研究为从免疫学角度区分两类患者提供了理论依据。
BackgroundAlthough much progress has been made in the diagnosis of early-stage lung adenocarcinoma (ES-LUAD), the prognosis for ES-LUAD patients with rapid recurrence is still poor. Importantly, there is currently no effective and precise method to screen patients who may develop rapid recurrence. Therefore, it is necessary to identify potential differentially expressed genes (DEGs) in ES-LUAD patients with rapid recurrence and non-rapid recurrence.MethodsAffymetrix GeneChip Human Transcriptome Array was used to identify DEGs between ES-LUAD patients with rapid recurrence and non-rapid recurrence. Rapid recurrence was defined as recurrence-free survival (RFS) ≦ 1 year and non-rapid recurrence was defined as RFS ≧ 3 years. The biological functions of the DEGs were analyzed by GO and KEGG pathway enrichment analyses. The protein–protein interaction (PPI) network of identified DEGs was conducted by STRING and Cytoscape software. The expression level of crucial hub genes and tumor-infiltrating lymphocytes (TILs) was verified by immunohistochemistry (IHC).ResultsA total of 416 DEGs were identified between ES-LUAD patients with and without rapid recurrence. The results of GO analysis revealed that 2 of the top 10 categories in the domain of cellular component, 2 of the top 10 in the domain of molecular function, and 9 of the top 10 in the domain of biological process were functionally related to immunity. The results of KEGG analysis showed that 6 of the top 8 pathways were functionally involved in immune regulation and inflammatory response. The PPI network analysis identified ten crucial nodal protein, including EGFR, MMP9, IL-1β, PTGS2, MMP1, and 5 histone proteins, which constituted 25 key interactions. IL-1β and PTGS2 expression were closely related to immunity and IHC analysis further revealed that low expression of IL-1β and PTGS2 is associated with rapid recurrence. Kaplan–Meier analysis further revealed that LUAD patients with lower IL-1β or PTGS2 expression had a worse RFS. When the TIL density of CD3+, CD4+, CD8+and CD20+subsets was less than 20%, ES-LUAD patients have a higher probability of rapid recurrence.ConclusionThere were significant differences in the expression of immune-related genes between patients with rapid recurrence and patient with non-rapid recurrence. Immune-related genes such as IL-1β and PTGS2 and TIL density (20%) play important roles in rapid recurrence of ES-LUAD. This study provided a theoretical basis for distinguishing the two types of patients from an immunological perspective.