Analysis Of The Effects Of CA4 And AGER On Survival Of Lung Adenocarcinoma And Their Possible Pathways Based On Bioinformatics

ObjectiveThe aim of our study was to screen CA4(carbonic anhydrase 4)gene and AGER(advanced glycosylation end-product specific receptor)gene based on bioinformatics database and analyze the relationship between their expression and patients' clinical characteristics and survival prognosis,and to explore their possible signaling pathways.Methods(1)We screened differential gene expression between lung adenocarcinoma and normal lung tissue in the GEO database,and the candidate genes were screened through the database;we analyzed the relationship between candidate genes and survival prognosis of the patients in the GEPIA database.(2)In the GEPIA database,we analyze the expression levels of CA4 and AGER genes in different tumors,and the relationship between its expression and survival results were also analyzed.In the GEPIA database,we can analyze the transcriptional expression levels of the two candidate genes between in lung adenocarcinoma and in normal lung tissues.In the CPTAC database in the ULCAN platform,we can analyze the protein expression levels of the two candidate genes between lung adenocarcinoma and normal lung tissues.In the LCE database,we can analyze the differential expression of the two genes in lung adenocarcinoma and normal lung tissues by using the meta-analysis and the correlation of expression of the two genes with the survival prognosis of the patients with lung adenocarcinoma by using the same methods.(3)The genes which closely related to the expression of the two candidate genes were analyzed based on Linkedomics database,and these genes which involved in possible signaling pathways were analyzed by using enrichment analysis.The CA4 and AGER gene expression and clinical characteristics data and expression data of genes related to their pathway were downloaded from TCGA database.The correlation between the expression of the two genes in lung adenocarcinoma was also analyzed based on GEPIA database.(4)In lung adenocarcinoma dataset,the CA4 and AGER gene expression was divided into high expression group and low expression group by using the best cut-off point analysis,and then were divided into four subgroups.The relationship among single gene group and gene subgroup and clinical characteristics were compared and analyzed to screen out statistically significant subgroups.The two independent samples T-test was used to screen out differential expression genes that affect the CA4 and AGER gene expression,and unconditional logistic regression to analyze the critical genes that may affect the expression of the CA4 and AGER genes.Results(1)The fourty intersecting genes are differentially expressed in lung adenocarcinoma and normal lung tissue.The fourty intersecting genes of lung adenocarcinoma were subjected to survival analysis one by one,and CA4 and AGER genes were statistically significant association with overall survival and disease-free survival time of patients.(2)The expression of CA4 and AGER genes was generally lower in tumor tissues than in the corresponding normal tissues.AGER gene expression was higher in cholangiocarcinoma and renal clear cell carcinoma than in their normal tissues.In lung adenocarcinoma,CA4 and AGER gene expression were correlated with survival prognosis of the patients(P < 0.05).In lung adenocarcinoma,both candidate gene m RNA and protein expression levels were lower than those in normal lung tissues(P < 0.01).Multi-dataset meta-analysis showed that CA4 and AGER genes were lowly expressed in lung adenocarcinoma and were correlated with survival prognosis of the patients.(3)The signaling pathway enrichment analysis showed that the two genes may be associated with cell cycle pathways.In lung adenocarcinoma dataset,CA4 and AGER gene expression were correlated with survival status and tumor T-stage of the patients,the correlation was statistically significant differences(P < 0.05).There was a correlation between CA4 and AGER with R = 0.73,and P value was less than 0.01.(4)In lung adenocarcinoma,the overall survival time of the patients with CA4 and AGER co-high expression was significantly higher than that of the two-gene co-low expression.RBL1,RBL2,CDKN2 B,STAT5A were the central genes which affecting CA4+AGER co-expression.Conclusion(1)CA4 and AGER genes play oncogenic roles in lung adenocarcinoma.(2)The survival prognosis of CA4 co-expressed with the AGER gene was better than that of a single gene and other combined subgroups.(3)The effect of CA4 and AGER genes on tumor T-stage may act through RBL1,RBL2,CDKN2 B,and STAT5 A genes.(4)The overall survival time of the patients with CA4 and AGER gene co-high expression was significantly higher than that of the two gene co-low expression groups,and the increased expression of RBL2,CDKN2 B,and STAT5 A genes mainly affected CA4+AGER co-high expression,while the high expression of RBL1 gene mainly affected CA4+AGER co-low expression.