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Identification key genes, key miRNAs and key transcription factors of lung adenocarcinoma.

ABSTRACT: BackgroundLung adenocarcinoma (LUAD) is one of the most common cancers worldwide. The etiology and pathophysiology of LUAD remain unclear. The aim of the present study was to identify the key genes, miRNAs and transcription factors (TFs) associated with the pathogenesis and prognosis of LUAD.MethodsThree gene expression profiles (GSE43458, GSE32863, GSE74706) of LUAD were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by GEO2R.The Gene Ontology (GO) terms, pathways, and protein-protein interactions (PPIs) of these DEGs were analyzed. Bases on DEGs, the miRNAs and TFs were predicted. Furthermore, TF-gene-miRNA co-expression network was constructed to identify key genes, miRNAs and TFs by bioinformatic methods. The expressions and prognostic values of key genes, miRNAs and TFs were carried out through The Cancer Genome Atlas (TCGA) database and Kaplan Meier-plotter (KM) online dataset.ResultsA total of 337 overlapped DEGs (75 upregulated and 262 downregulated) of LUAD were identified from the three GSE datasets. Moreover, 851 miRNAs and 29 TFs were identified to be associated with these DEGs. In total, 10 hub genes, 10 key miRNAs and 10 key TFs were located in the central hub of the TF-gene-miRNA co-expression network, and validated using The Cancer Genome Atlas (TCGA) database. Specifically, seven genes (PHACTR2, MSRB3, GHR, PLSCR4, EPB41L2, NPNT, FBXO32), two miRNAs (hsa-let-7e-5p, hsa-miR-17-5p) and four TFs (STAT6, E2F1, ETS1, JUN) were identified to be associated with prognosis of LUAD, which have significantly different expressions between LUAD and normal lung tissue. Additionally, the miRNA/gene co-expression analysis also revealed that hsa-miR-17-5p and PLSCR4 have a significant negative co-expression relationship (r=?0.33, P=1.67e-14) in LUAD.ConclusionsOur study constructed a regulatory network of TF-gene-miRNA in LUAD, which may provide new insights about the interaction between genes, miRNAs and TFs in the pathogenesis of LUAD, and identify potential biomarkers or therapeutic targets for LUAD.

SUBMITTER: Li J

PROVIDER: S-EPMC7330310 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Project description:Background:The development of human tumors is associated with the abnormal expression of various functional genes, and a massive tumor-based database needs to be deeply mined. Based on a multigene prediction model, access to urgent prognosis of patients has become possible. Materials and Methods:We selected three RNA expression profiles (GSE32863, GSE10072, and GSE43458) from the lung adenocarcinoma (LUAD) database of the Gene Expression Omnibus (GEO) and analyzed the differentially expressed genes (DEGs) between tumor and normal tissue using GEO2R program. After that, we analyzed the transcriptome data of 479 LUAD samples (54 normal tissue samples and 425 cancer tissue samples) and their clinical follow-up data from the (TCGA) database. Kaplan-Meier (KM) curve and receiver operating characteristic (ROC) were used to assess the prediction model. Multivariate Cox analysis was used to identify independent predictors. TCGA pancreatic adenocarcinoma datasets were used to establish a nomogram model. Results:We found 98 significantly prognosis-related genes using KM and COX analysis, among which six genes were found to be the DEGs in GEO. Using multivariate analysis, it was found that a single gene could not be used as an independent predictor of prognosis. However, the risk score calculated by weighting these six genes could serve as an independent prognosis predictor. COX analysis performed with multiple covariates such as age, gender, tumor stage, and TNM typing showed that risk score could still be utilized as an independent risk factor for patient survival rate (p = 0.013) and had an applicable reliability (area under the curve, AUC = 0.665). By combining risk score and various clinical features, the nomogram model was constructed, which had been proven to have high consistency for the prediction of 3- and 5-year survival rate (concordance = 0.751) and high accuracy as tested by ROC (AUC = 0.71;AUC = 0.708). Conclusion:We proposed a method to predict the prognosis of LUAD by weighting multiple genes and constructed a nomogram model suitable for the prognostic evaluation of LUAD, which could provide a new tool for the identification of therapeutic targets and the efficacy evaluation of LUAD.

Project description:BackgroundCD8+ T cells are one of the central effector cells in the immune microenvironment. CD8+ T cells play a vital role in the development and progression of lung adenocarcinoma (LUAD). This study aimed to explore the key genes related to CD8+ T-cell infiltration in LUAD and to develop a novel prognosis model based on these genes.MethodsWith the use of the LUAD dataset from The Cancer Genome Atlas (TCGA), the differentially expressed genes (DEGs) were analyzed, and a co-expression network was constructed by weighted gene co-expression network analysis (WGCNA). Combined with the CIBERSORT algorithm, the gene module in WGCNA, which was the most significantly correlated with CD8+ T cells, was selected for the subsequent analyses. Key genes were then identified by co-expression network analysis, protein-protein interactions network analysis, and least absolute shrinkage and selection operator (Lasso)-penalized Cox regression analysis. A risk assessment model was built based on these key genes and then validated by the dataset from the Gene Expression Omnibus (GEO) database and multiple fluorescence in situ hybridization experiments of a tissue microarray.ResultsFive key genes (MZT2A, ALG3, ATIC, GPI, and GAPDH) related to prognosis and CD8+ T-cell infiltration were identified, and a risk assessment model was established based on them. We found that the risk score could well predict the prognosis of LUAD, and the risk score was negatively related to CD8+ T-cell infiltration and correlated with the advanced tumor stage. The results of the GEO database and tissue microarray were consistent with those of TCGA. Furthermore, the risk score was higher significantly in tumor tissues than in adjacent lung tissues and was correlated with the advanced tumor stage.ConclusionsThis study may provide a novel risk assessment model for prognosis prediction and a new perspective to explore the mechanism of tumor immune microenvironment related to CD8+ T-cell infiltration in LUAD.

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Identification key genes, key miRNAs and key transcription factors of lung adenocarcinoma.

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