关键词: 肺肿瘤, 关键基因, 上皮-间质转化, 免疫浸润, 预后因子, 腺癌

Abstract:

Objective To screen out the key genes affecting lung adenocarcinoma （LUAD） through bioinformatics methods，and to analyze their biological functions and the influences on the LUAD prognosis. Methods The GSE118370 and GSE136043 chip data were downloaded from the Gene Expression Omnibus（GEO） Database. The LUAD-related data were selected from the The Cancer Genome Atlas（TCGA） Database. R software was used to analyze the co-expressed differentially expressed genes （DEGs）； clusterProfile R package was utilized for Gene Ontology （GO） functional enrichment analysis； DAVID Database was used for the Kyoto Gene and Genome Encyclopedia （KEGG） signaling pathway enrichment analysis； STRING Database was used to construct the protein-protein interaction （PPI） network； Cytoscape was used to screen out the top 10 key genes； GEPIA Database and Human Protein Atlas（HPA） Database were used to analyze the expressions of key genes mRNA and protein in normal lung tissue and LUAD tissue， and their expressions in LUAD tissues with different stages；immune infiltration analysis and survival analysis were used to analyze the correlation between the expressions of key genes and the survival time of the patients. Results In total， 428 DEGs were screened out. The GO functional analysis results showed that the DEGs of LUAD were mainly enriched in biological process（BP） such as epithelial-mesenchymal transition （EMT）， cellular component（CC） such as the cell base， and molecular function（MF） such as extracellular matrix （ECM） structure formation.The KEGG signaling pathway analysis results showed that the DEGs of LUAD were mainly enriched in the pathways like cytokine receptor interactions.topoisomerase Ⅱ alpha（TOP2A），abnormal spindle microtubule assembly（ASPM），cyclin B1，（CCNB1），cell division cycle associated 8（CDCA8），baculoviral IAP repeat containing 5（BIRC5），aurora A（AURKA），kinesin family member 20A（KIF20A），centrosomal protein 55（CEP55），centromere protein F（CENPF），and targeting protein for xklp2（TPX2） were selected as the key genes. Compared with normal lung tissue， the expression levels of TOP2A， CCNB1， CDCA8， BIRC5， AURKA， KIF20A， CEP55， CENPF， and TPX2 mRNA in lung tissue of the LUAD patients were increased （P<0.01）， and the expression levels of TOP2A， CCNB1， CDCA8， BIRC5， AURKA， KIF20A， CEP55， CENPF， and TPX2 proteins were increased. There were significant differences in the expression levels of CCNB1， CDCA8， BIRC5， AURKA， KIF20A， CEP55， and TPX2 mRNA in the LUAD tissue with different stages （P<0.01）. Compared with the LUAD patients with stage Ⅰ，stage Ⅱ，and stage Ⅲ，the expression levels of CCNB1， CDCA8， AURKA， KIF20A， CEP55， and TPX2 mRNA in lung tissue of the LUAD patients with stage Ⅳ were increased（P<0.01）； compared with the LUAD patients with stage Ⅰ，stage Ⅱ， and stage Ⅳ，the expression level of BIRC5 mRNA in lung tissue of the LUAD patients with stage Ⅲ was increased （P<0.01）. The expressions of 10 key genes were negatively correlated with the B-lymphocyte infiltration （－0.253≤r≤－0.014， P<0.01）； the expressions of TOP2A， ASPM， CDCA8， BIRC5， CEP55， CENPF， and TPX2 were positively correlated with the neutrophil infiltration （0.049≤r≤0.165，P<0.01）； the expressions of CCNB1 and AURKA were negatively correlated with the CD4 T lymphocyte， macrophage， and dendritic cell infiltration （－0.210≤r≤－0.100，P<0.01）. The high expression of CDCA8 increased the risk of LUAD deterioration （P<0.01）， and the high expressions of TOP2A， CCNB1， CDCA8， BIRC5， AURKA， KIF20A， CEP55， CENPF， and TPX2 increased the death risk of the patients（P<0.01）. Conclusion TOP2A， ASPM， CCNB1， CDCA8， BIRC5， AURKA， KIF20A， CEP55， CENPF， and TPX2 are the key genes involved in the development and progression of LUAD. They may promote the development of LUAD by accelerating the EMT process， and their high expressions suggest the poor prognosis and elevate the death risk of the LUAD patients.

Key words: Lung adenocarcinoma, Key gene, Epithelial-mesenchymal transition, Immune infiltration, Prognostic factor, Adenocarcinoma