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中华移植杂志(电子版) ›› 2021, Vol. 15 ›› Issue (06) : 353 -358. doi: 10.3877/cma.j.issn.1674-3903.2021.06.006

论著

肺移植缺血再灌注损伤差异表达基因的生物信息学分析
郭强1, 童松1, 吴创炎1, 陈重瑞1, 吴特1, 王思桦1,()   
  1. 1. 430022 武汉,华中科技大学同济医学院附属协和医院胸外科
  • 收稿日期:2021-11-02 出版日期:2021-12-25
  • 通信作者: 王思桦
  • 基金资助:
    国家自然科学基金青年基金项目(82100115,82100116); 国家自然科学基金面上项目(82070431)

The roles and potential mechanisms of differential genes in lung transplantation ischemia-reperfusion injury based on geno expression omnibus database

Qiang Guo1, Song Tong1, Chuangyan Wu1, Chongrui Chen1, Te Wu1, Sihua Wang1,()   

  1. 1. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
  • Received:2021-11-02 Published:2021-12-25
  • Corresponding author: Sihua Wang
引用本文:

郭强, 童松, 吴创炎, 陈重瑞, 吴特, 王思桦. 肺移植缺血再灌注损伤差异表达基因的生物信息学分析[J/OL]. 中华移植杂志(电子版), 2021, 15(06): 353-358.

Qiang Guo, Song Tong, Chuangyan Wu, Chongrui Chen, Te Wu, Sihua Wang. The roles and potential mechanisms of differential genes in lung transplantation ischemia-reperfusion injury based on geno expression omnibus database[J/OL]. Chinese Journal of Transplantation(Electronic Edition), 2021, 15(06): 353-358.

目的

基于微阵列数据分析肺移植缺血再灌注损伤(IRI)相关基因的作用和潜在机制。

方法

通过基因表达综合数据库官方网站下载GSE127003和GSE127055数据集的矩阵文件,并进行数据处理和校正。利用limma包分析GSE127003数据集中冷缺血和缺血再灌注组织的基因表达水平,以P<0.05和logFC绝对值>1作为肺移植IRI相关差异表达基因(DEGs)的筛选标准。通过基因本体(GO)注释及京都基因和基因组百科全书(KEGG)通路分析研究肺移植IRI相关DEGs涉及的生物学作用和潜在信号通路,以P<0.05为筛选标准。使用STRING数据库构建肺移植IRI相关DEGs蛋白-蛋白相互作用(PPI)网络并筛选PPI网络中关键基因。在GSE127055数据集冷缺血和缺血再灌注样本中鉴定关键基因的RNA表达水平,P<0.05为差异有统计学意义。

结果

与冷缺血样本相比,缺血再灌注样本中的DEGs有114个,过表达112个,低表达2个。KEGG通路分析结果显示,肺移植IRI相关DEGs涉及TNF、IL-17、核因子κB、细胞因子-细胞因子受体相互作用、C型凝集素受体、丝裂原活化蛋白激酶、趋化因子和Toll样受体等信号通路。GO注释结果显示,肺移植IRI相关DEGs涉及白细胞活化调节、细胞因子产生、T细胞活化、IL-8生成、自然杀伤细胞趋化性及CC趋化因子受体结合等生物学功能。PPI网络中的关键基因经GSE127055数据集验证,相比于冷缺血样本,TNF、IL1B、C-X-C基序趋化因子配体(CXCL)8、CXCL1、前列腺素内过氧化物合酶2(PTGS2)和IL1A在缺血再灌注样本中的表达水平均升高,差异均有统计学意义(P均<0.05)。

结论

TNF、IL1B、CXCL8、CXCL1、IL1A和PTGS2基因表达与肺移植IRI有关。

Objective

To analyze the roles and potential mechanisms of lung transplantation ischemia-reperfusion injury (IRI) related genes based on microarray data.

Methods

The matrix files of the GSE127003 and GSE127055 datasets were downloaded through the gene expression omnibus database. The gene expression levels of cold ischemia and ischemia-reperfusion tissues in the GSE127003 dataset were analyzed using the limma package, and P<0.05 and absolute logFC >1 were used as screening criteria for IRI-related differentially expressed genes (DEGs) in lung transplantation. The biological roles and potential signaling pathways involved in IRI-related DEGs in lung transplantation were studied by gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, with P<0.05 as the screening criterion. The STRING database was used to construct the protein-protein interactions (PPI) network of IRI-associated DEGs in lung transplantation and screen the key genes in the PPI network. The RNA expression levels of key genes were identified in the GSE127055 data intensive ischemia and ischemia-reperfusion samples, and P<0.05 was considered statistically significant.

Results

There were 114 DEGs in the ischemia-reperfusion samples compared to the cold ischemia samples, 112 were overexpressed, and 2 were underexpressed in ischemia-reperfusion samples compared with cold ischemia samples. The results of KEGG pathway analysis showed that IRI-related DEGs in lung transplantation involved signaling pathways such as TNF, IL-17, nuclear factor-κB, cytokine-cytokine receptor interaction, C-type lectin receptor, mitogen-activated protein kinase (MAPK), chemokines, and Toll-like receptors. GO annotation results showed that IRI-related DEGs in lung transplantation involved biological functions such as leukocyte activation regulation, cytokine production, T cell activation, IL-8 production, natural killer cell chemotaxis and CC chemokine receptor binding. Key genes in the PPI network were validated by the GSE127055 dataset, and the expression levels of TNF, IL1B, C-X-C motif chemokine ligand (CXCL) 8, CXCL1, prostaglandin-endoperoxide synthase 2 (PTGS2) and IL1A were increased in ischemia-reperfusion samples compared with cold ischemia samples, and the differences were statistically significant (all P<0.05).

Conclusion

The expressions of TNF, IL1B, CXCL8, CXCL1, IL1A and PTGS2 are related to lung transplantation IRI.

图1 肺移植缺血再灌注损伤相关的前20位过表达差异基因热图
图2 肺移植缺血再灌注损伤相关的差异表达基因火山图注:红色为过表达基因;绿色为低表达基因;黑色为表达无差异的基因
图3 肺移植缺血再灌注损伤相关差异表达基因涉及的生物学功能和信号通路注:KEGG.京都基因和基因组百科全书;NF-κB.核因子κB; AGE.晚期糖基化终末产物;RAGE.晚期糖基化终末产物受体;a. KEGG通路分析;b.生物学过程;c.细胞组分;d.分子功能
表1 KEGG通路分析肺移植缺血再灌注损伤相关差异表达基因涉及的信号通路
通路ID 描述 错误发现率
hsa04668 TNF信号通路 2.52E-16
hsa04657 IL-17信号通路 3.10E-12
hsa04064 NF-κB信号通路 7.80E-12
hsa05144 疟疾 3.70E-10
hsa05323 类风湿关节炎 6.41E-10
hsa04060 细胞因子-细胞因子受体相互作用 1.07E-08
hsa04061 病毒蛋白与细胞因子和细胞因子受体的相互作用 1.96E-08
hsa05134 军团菌病 2.09E-08
hsa04933 AGE-RAGE信号通路在糖尿病并发症中的作用 2.43E-07
hsa05143 非洲锥虫病 4.08E-07
hsa04625 C型凝集素受体信号通路 3.93E-06
hsa05164 甲型流感 2.74E-05
hsa04621 NOD样受体信号通路 4.46E-05
hsa05132 沙门氏菌感染 6.66E-05
hsa05332 移植物抗宿主病 2.73E-04
hsa05418 流体剪切应力和动脉粥样硬化 2.73E-04
hsa05142 南美锥虫病 2.73E-04
hsa04010 MAPK信号通路 4.25E-04
hsa05133 百日咳 4.28E-04
hsa04380 破骨细胞分化 9.92E-04
hsa04978 矿物质吸收 1.12E-03
hsa05020 朊粒病 1.66E-03
hsa04062 趋化因子信号通路 1.66E-03
hsa05321 炎症性肠病 1.67E-03
hsa05146 阿米巴病 1.67E-03
hsa04620 Toll样受体信号通路 1.79E-03
hsa05169 巴尔病毒感染 2.14E-03
hsa04940 Ⅰ型糖尿病 2.99E-03
hsa05163 人类CMV感染 4.22E-03
hsa05162 麻疹 6.93E-03
hsa04640 造血细胞谱系 8.53E-03
hsa04932 非酒精性脂肪肝 9.61E-03
hsa04623 细胞溶质DNA传感通路 1.07E-02
hsa01523 抗叶酸抗性 1.15E-02
hsa04630 JAK-STAT信号通路 1.31E-02
hsa05145 弓形虫病 1.31E-02
hsa05166 人类T细胞白血病病毒1型感染 1.31E-02
hsa05120 幽门螺杆菌感染中的上皮细胞信号传导 1.36E-02
hsa04141 内质网中的蛋白质加工 1.36E-02
hsa05135 耶尔森菌感染 1.60E-02
hsa05140 利什曼病 1.71E-02
hsa05167 卡波西肉瘤相关疱疹病毒感染 2.14E-02
hsa05202 癌症中的转录失调 2.14E-02
hsa04210 细胞凋亡 2.46E-02
hsa04218 细胞衰老 4.66E-02
hsa04217 坏死性凋亡 4.79E-02
图4 肺移植缺血再灌注损伤相关差异表达基因构建的蛋白-蛋白相互作用网络中关键基因
图5 肺移植缺血再灌注损伤相关关键基因在GSE127055数据集中的表达情况注:CXCL. C-X-C基序趋化因子配体;PTGS2.前列腺素内过氧化物合酶2; *. P<0.05
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