Bioinformatics Analysis Of The Relationship Between The Abnormal Expression Of NEDD8 In Lung Adenocarcinoma And Clinical Features,Prognosis And Functional Enrichment

Objective:Lung cancer is the second most frequent cancer worldwide,accounting for the largest proportion of cancer-related deaths,and lung adenocarcinoma is the most prevalent lung cancer subtype.The incidence of lung cancer is associated with factors such as gender,age,smoking,and environment,and early screening is extremely important for the diagnosis and treatment of lung cancer.With the progress of research on the molecular mechanisms of lung cancer,novel therapeutic modalities are gradually being applied,including targeted therapy and immunotherapy.Therefore,it is particularly important to explore the molecular mechanisms of lung adenocarcinoma and to explore more reliable molecular screening tools,targeted therapeutic targets and immunotherapeutic approaches.Neural precursor cell expressed developmentally downregulated 8(NEDD8)is a ubiquitin-like protein involved in the post-translational modification process of Neddylation.NEDD8 is expressed in NEDD8-activating enzyme E1,NEDD8 has been found to be aberrantly expressed in a variety of cancers,but its role in lung adenocarcinoma remains to be further investigated.In this study,we investigated the molecular biological functions of NEDD8 in lung adenocarcinoma by integrating data from multiple databases through a combination of bioinformatics techniques and statistical analysis,and performed a comprehensive analysis of the expression,diagnostic value,prognostic prediction,functional enrichment and immune infiltration of NEDD8 in lung adenocarcinoma.Methods:The pan-cancer tissue data in the TCGA database were downloaded and collated,and the differences in NEDD8 expression between tumor and paraneoplastic tissues in the TCGA database were analyzed using the R package,and the differences in the degree of NEDD8 expression between tumor and normal tissues were further verified by combining the data from normal tissues in GTEx.To verify the diagnostic value of NEDD8 for lung adenocarcinoma,ROC diagnostic curves were plotted.Subsequently,univariate and multifactorial analyses were applied to explore the effect of NEDD8 on the prognosis of lung adenocarcinoma patients,and survival curves were generated using the Kaplan-Meier Plotter database.By further analyzing the clinicopathological characteristics and prognosis of patients,a lung adenocarcinoma prediction model was constructed,and the relationship between each predictor variable was demonstrated using column line plots to calculate the probability of patient survival.Meanwhile,co-expressed genes of NEDD8 were screened and correlation heat maps were drawn.To explore the cellular function of NEDD8 in lung adenocarcinoma,KEGG/GO analysis and GSEA functional enrichment analysis were used.The CPTAC database was analyzed using UALCAN to explore the relationship between NEDD8 and aberrant signaling pathways in lung adenocarcinoma.In addition,the relationship between NEDD8 and immune cell infiltration in lung adenocarcinoma tissues was analyzed in this study.Finally,the protein expression and distribution of NEDD8 in pathological tissues of lung adenocarcinoma and in normal lung tissues were observed by pathological sections in the HPA database.Results:(1)NEDD8 was aberrantly expressed in a variety of cancers,and the expression of NEDD8 was significantly higher in lung adenocarcinoma(p<;0.001).(2)The ROC curve of NEDD8 for the diagnosis of lung adenocarcinoma showed that the area under the curve was 0.721(CI 0.660-0.783),indicating that NEDD8 has a good diagnostic value for lung adenocarcinoma.(3)Kaplan-Meier Plotter analysis showed that in lung adenocarcinoma,the overall survival(overall survival,OS)and first progression(FP)were significantly shorter in the high NEDD8 expression group than in the low NEDD8 expression group(P<0.001,P<0.01).(4)Univariate analysis showed that high NEDD8 expression was significantly negatively correlated with patient OS(p<0.05).Multifactorial analysis showed that NEDD8 level,T-stage,N-stage,and initial treatment outcome were independent prognostic factors for lung adenocarcinoma.(5)Gene correlation results showed that the top 10 genes with positive differential expression of NEDD8 were MRPL52,DAD1,PSMB5,ERH,C14orf119,NGDN,TIMM9,ATP5MPL,COA8,SLIRP.the top 10 genes with negative differential expression of NEDD8 were TNXB,PLCG2,CACNA1C,XCR1,KCNA2,AKNA,PTK2B,RYR2,TRANK1,and DNAH1.(6)KEGG/GO biofunctional analysis showed that NEDD8 was closely associated with proteasome metabolism and cell cycle transition in lung adenocarcinoma;GSEA enrichment analysis showed that NEDD8 was associated with several gene expression and cell cycle function pathways in lung adenocarcinoma.(7)Analysis of aberrant signaling pathways in lung adenocarcinoma showed that NEDD8 expression was significantly higher in lung adenocarcinoma tissues with aberrant expression of the HIPPO pathway,aberrant expression of the WNT pathway,aberrant expression of the mTOR pathway,and aberrant expression of the RTK pathway compared to signaling pathways that did not experience aberrant expression.However,for the NRF2 pathway and p53/Rb-related pathway,there was no significant difference in NEDD8 expression between lung adenocarcinoma tissues with aberrant expression of the pathway and those without aberrant expression of the pathway.(8)Analysis of immune cell infiltration in lung adenocarcinoma showed that NEDD8 was negatively correlated with infiltration of multiple immune cells,with Tcm,Tem,eosinophils,mast cells,NK cells,B cells and T cells being the immune cells most affected by NEDD8 levels.(9)A search of the HPA database showed that NEDD8 staining was more intense and the percentage of stained cells was higher in lung adenocarcinoma tissues compared to normal lung tissuesConclusion:NEDD8 expression was elevated in lung adenocarcinoma,significantly correlated with patient OS and FP shortening,and was an independent risk factor for OS in lung adenocarcinoma patients.The diagnostic ROC curve showed that NEDD8 has a good diagnostic effect on lung adenocarcinoma and is expected to be a diagnostic indicator for lung adenocarcinoma.NEDD8 was significantly associated with several cell cycle-related functions and with alterations in several cell signaling pathways in lung adenocarcinoma.NEDD8 was significantly negatively correlated with multiple immune cell infiltrations and has a potential impact on the formation of immune microenvironment in lung adenocarcinoma.