Abstract
BackgroundCompeting endogenous RNAs (ceRNAs) are a newly identified type of regulatory RNA. Accumulating evidence suggests that ceRNAs play an important role in the pathogenesis of diseases such as cancer. Thus, ceRNA dysregulation may represent an important molecular mechanism underlying cancer progression and poor prognosis. In this study, we aimed to identify ceRNAs that may serve as potential biomarkers for early diagnosis of lung adenocarcinoma (LUAD).MethodsWe performed differential gene expression analysis on TCGA-LUAD datasets to identify differentially expressed (DE) mRNAs, lncRNAs, and miRNAs at different tumor stages. Based on the ceRNA hypothesis and considering the synergistic or feedback regulation of ceRNAs, a lncRNA–miRNA–mRNA network was constructed. Functional analysis was performed using gene ontology term and KEGG pathway enrichment analysis and KOBAS 2.0 software. Transcription factor (TF) analysis was carried out to identify direct targets of the TFs associated with LUAD prognosis. Identified DE genes were validated using gene expression omnibus (GEO) datasets.ResultsBased on analysis of TCGA-LUAD datasets, we obtained 2,610 DE mRNAs, 915 lncRNAs, and 125 miRNAs that were common to different tumor stages (|log2(Fold change)| ≥ 1, false discovery rate < 0.01), respectively. Functional analysis showed that the aberrantly expressed mRNAs were closely related to tumor development. Survival analyses of the constructed ceRNA network modules demonstrated that five of them exhibit prognostic significance. The five ceRNA interaction modules contained one lncRNA (FENDRR), three mRNAs (EPAS1, FOXF1, and EDNRB), and four miRNAs (hsa-miR-148a, hsa-miR-195, hsa-miR-196b, and hsa-miR-301b). The aberrant expression of one lncRNA and three mRNAs was verified in the LUAD GEO dataset. Transcription factor analysis demonstrated that EPAS1 directly targeted 13 DE mRNAs.ConclusionOur observations indicate that lncRNA-related ceRNAs and TFs play an important role in LUAD. The present study provides novel insights into the molecular mechanisms underlying LUAD pathogenesis. Furthermore, our study facilitates the identification of potential biomarkers for the early diagnosis and prognosis of LUAD and therapeutic targets for its treatment.
Highlights
Lung cancer, which is one of the most common malignancies worldwide, poses a serious threat to human health and life (Jemal et al, 2011; Torre et al, 2015)
Expressed RNAs in lung adenocarcinoma (LUAD) Among the LUAD datasets, expression data for 19,669 mRNAs, 7,309 lncRNAs, and 1,882 miRNAs were extracted from TCGA and analyzed with R package (DESeq2)
We found that EPAS1 and FOXF1 showed a high degree of representation in the Competing endogenous RNAs (ceRNAs) network
Summary
Lung cancer, which is one of the most common malignancies worldwide, poses a serious threat to human health and life (Jemal et al, 2011; Torre et al, 2015). Lung cancer is difficult to diagnose early and associated with poor prognosis and low survival rate (Bernaudin, 2010; Hardavella, George & Sethi, 2016; Onganer, Seckl & Djamgoz, 2005; Prim et al, 2010; Reinmuth et al, 2014; Tamura et al, 2015). Methods: We performed differential gene expression analysis on TCGA-LUAD datasets to identify differentially expressed (DE) mRNAs, lncRNAs, and miRNAs at different tumor stages. Results: Based on analysis of TCGA-LUAD datasets, we obtained 2,610 DE mRNAs, 915 lncRNAs, and 125 miRNAs that were common to different tumor stages (|log2(Fold change)| ! Transcription factor analysis demonstrated that EPAS1 directly targeted 13 DE mRNAs. Conclusion: Our observations indicate that lncRNA-related ceRNAs and TFs play an important role in LUAD. Our study facilitates the identification of potential biomarkers for the early diagnosis and prognosis of LUAD and therapeutic targets for its treatment
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