Integrated analysis of dysregulated long non-coding RNAs/microRNAs/mRNAs in metastasis of lung adenocarcinoma

Abstract

Background: Lung adenocarcinoma (LUAD), largely remains a primary cause of cancer-related death worldwide. The molecular mechanisms in LUAD metastasis have not been completely uncovered.

Methods: In this study, we identified differentially expressed genes (DEGs), miRNAs (DEMs) and lncRNAs (DELs) underlying metastasis of LUAD from The Cancer Genome Atlas database. Intersection mRNAs were used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and co-expression network analysis. In addition, survival analyses of intersection mRNAs were conducted. Finally, intersection mRNAs, miRNAs and lncRNAs were subjected to construct miRNA-mRNA-lncRNA network.

Results: A total of 1015 DEGs, 54 DEMs and 22 DELs were identified in LUAD metastasis and non-metastasis samples. GO and KEGG pathway analysis had proven that the functions of intersection mRNAs were closely related with many important processes in cancer pathogenesis. Among the co-expression interactions network, 22 genes in the co-expression network were over the degree 20. These genes imply that they have connections with many other gene nodes. In addition, 14 target genes (ARHGAP11A, ASPM, HELLS, PRC1, TMPO, ARHGAP30, CD52, IL16, IRF8, P2RY13, PRKCB, PTPRC, SASH3 and TRAF3IP3) were found to be associated with survival in patients with LUAD significantly (log-rank P < 0.05). Two lncRNAs (LOC96610 and ADAM6) acting as ceRNAs were identified based on the miRNA-mRNA-lncRNA network.

Conclusions: Taken together, the results may provide a novel perspective to develop a multiple gene diagnostic tool for LUAD prognosis, which might also provide potential biomarkers or therapeutic targets for LUAD.

Keywords: Biomarker; Lung adenocarcinoma; Metastasis; lncRNAs.

Fig. 1

Flow chart of bioinformatics analysis

Fig. 2

Heatmap for hierarchical cluster analysis of DEGs, DEMs and DELs expression levels change between LUAD metastasis and non-metastasis tissues (a–c). Colors ranged from green (low expression) to red (high expression), representing the relative expression levels of DEGs, DEMs and DELs

Fig. 3

a, b Top 20 enrichment of GO terms for differentially expressed intersection genes (the bar plot shows the enrichment scores of the significant enrichment GO terms). c, d Top 20 enrichment of pathways for differentially expressed intersection genes (the bar plot shows the enrichment scores of the significant enrichment pathways)

Fig. 4

The co-expression network constructed by Cytoscape software. Proteins are represented with color nodes, and interactions are represented with edges. Red color indicated up-regulation; blue color indicated down-regulation

Fig. 5

Kaplan-Meier (KM) survival curves for 14 target genes. KM survival curves show significant OS or RFS survival differences between higher-expression levels and lower-expression levels of LUAD patients

Fig. 6

The receiver operating characteristic (ROC) curves for 14 target genes. The area under the curve (AUC) under binomial exact confidence interval was calculated to generate the ROC curve

Fig. 7

The miRNA-mRNA-lncRNA ceRNA network. Red balls represent up-regulated mRNAs, blue diamonds, down-regulated miRNAs, and red balls surrounded by yellow rings, up-regulated lncRNAs