Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for hepatocellular carcinoma

Abstract

Background: Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; therefore, lncRNAs are considered a major part of the competitive endogenous RNA (ceRNA) network and have attracted growing attention. The present study explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in hepatocellular carcinoma (HCC) and their potential impact on HCC patient prognosis.

Methods: In this study, we systematically studied the expression profiles and prognostic value of lncRNA, miRNA, and mRNA from a total of 838 HCC patients from five HCC cohorts (TCGA, GSE54236, GSE76427, GSE64041 and GSE14520). The TCGA, GSE54236 and GSE76427 HCC cohorts were utilized to establish a prognosis-related network of dysregulated ceRNAs by bioinformatics methods. The GSE64041 and GSE14520 HCC cohorts were utilized to verify the expression of candidate genes.

Results: In total, 721 lncRNAs, 73 miRNAs, and 1563 mRNAs were aberrantly expressed in HCC samples. A ceRNA network including 26 lncRNAs, four miRNAs, and six mRNAs specific to HCC was established. The survival analysis showed that four lncRNAs (MYCNOS, DLX6-AS1, LINC00221, and CRNDE) and two mRNAs (CCNB1 and SHCBP1) were prognostic biomarkers for patients with HCC in both the TCGA and GEO databases.

Conclusion: The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of HCC. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network can be further evaluated as potential therapeutic targets and prognostic biomarkers for HCC.

Keywords: Competing endogenous RNA; Hepatocellular carcinoma; Long noncoding RNA; MicroRNA; Prognosis.

Fig. 1

Heatmap plots of the differentially expressed genes (DEGs). Heatmap plots of the differentially expressed lncRNAs, miRNAs, and mRNAs in the 50 paired HCC samples (a) and 43 paired HCC samples (b). The left vertical axis presents the DEG clusters. The horizontal axis represents the samples. Sample clusters are presented above the horizontal axis. The vertical axis presents the DEGs. Blue denotes downregulated genes, and red denotes upregulated genes

Fig. 2

Sankey diagram for the ceRNA network in HCC. Each rectangle represents a gene, and the connection degree of each gene is visualized based on the size of the rectangle

Fig. 3

Survival analysis for DElncRNAs. Kaplan–Meier survival curves for DElncRNAs in the TCGA (a) and meta-GEO (b) HCC cohorts. The horizontal axis indicates the overall survival time in years, and the vertical axis indicates the survival rate

Fig. 4

Survival analysis for DEmiRNAs. Kaplan–Meier survival curves for DEmRNAs in the TCGA (a) and meta-GEO (b) HCC cohorts. The horizontal axis indicates the overall survival time in years, and the vertical axis indicates the survival rate. The expression pattern of DEmRNAs in the TCGA (c), GSE64041 (d) and GSE14520 (e) HCC cohorts of paired HCC samples. Gene set enrichment analysis of DEmRNAs (f)

Fig. 5

Survival analysis for DEmiRNAs. Kaplan–Meier survival curves for DEmiRNAs (a) and the ratios of DEmiRNAs to their target DEmRNAs (b) in the TCGA HCC cohorts. The horizontal axis indicates the overall survival time in years, and the vertical axis indicates the survival rate