Identification of lncRNA/circRNA-miRNA-mRNA ceRNA Network as Biomarkers for Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer, with the incidence and mortality rates increasing every year. Despite the improvement of clinical management, substantial challenges remain due to its high recurrence rates and short survival period. This study aimed to identify potential diagnostic and prognostic biomarkers in HCC through bioinformatic analysis.Methods: Datasets from GEO and TCGA databases were used for the bioinformatic analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out by WebGestalt website and clusterProfiler package of R. The STRING database and Cytoscape software were used to establish the protein-protein interaction (PPI) network. The GEPIA website was used to perform expression analyses of the genes. The miRDB, miRWalk, and TargetScan were employed to predict miRNAs and the expression levels of the predicted miRNAs were explored via OncomiR database. LncRNAs were predicted in the StarBase and LncBase while circRNA prediction was performed by the circBank. ROC curve analysis and Kaplan-Meier (KM) survival analysis were performed to evaluate the diagnostic and prognostic value of the gene expression, respectively.Results: A total of 327 upregulated and 422 downregulated overlapping DEGs were identified between HCC tissues and noncancerous liver tissues. The PPI network was constructed with 89 nodes and 178 edges and eight hub genes were selected to predict upstream miRNAs and ceRNAs. A lncRNA/circRNA-miRNA-mRNA network was successfully constructed based on the ceRNA hypothesis, including five lncRNAs (DLGAP1-AS1, GAS5, LINC00665, TYMSOS, and ZFAS1), six circRNAs (hsa_circ_0003209, hsa_circ_0008128, hsa_circ_0020396, hsa_circ_0030051, hsa_circ_0034049, and hsa_circ_0082333), eight miRNAs (hsa-miR-150-5p, hsa-miR-19b-3p, hsa-miR-23b-3p, hsa-miR-26a-5p, hsa-miR-651-5p, hsa-miR-10a-5p, hsa-miR-214-5p and hsa-miR-486-5p), and five mRNAs (CDC6, GINS1, MCM4, MCM6, and MCM7). The ceRNA network can promote HCC progression via cell cycle, DNA replication, and other pathways. Clinical diagnostic and survival analyses demonstrated that the ZFAS1/hsa-miR-150-5p/GINS1 ceRNA regulatory axis had a high diagnostic and prognostic value.Conclusion: These results revealed that cell cycle and DNA replication pathway could be potential pathways to participate in HCC development. The ceRNA network is expected to provide potential biomarkers and therapeutic targets for HCC management, especially the ZFAS1/hsa-miR-150-5p/GINS1 regulatory axis.

RNA-sep analysis of circular RNAs and ceRNA networks in human hepatocellular carcinoma

“…Accumulating evidence indicates that ceRNA regulatory networks play a role in the biological processes of HCC development, such as proliferation, metastasis, epithelial-to-mesenchymal transition (EMT), and chemoresistance [30] . In our study, we by performed sequencing analysis and constructed a total of 5 ceRNA network maps of highly expressed circRNAs that included 5 circRNAs, 15 miRNAs, and 278 mRNAs.…”

Function of the Long Noncoding RNAs in Hepatocellular Carcinoma: Classification, Molecular Mechanisms, and Significant Therapeutic Potentials

“…It is well known that ncRNAs account for the majority of the human transcriptome, including miRNAs, lncRNAs, and circRNAs. MicroRNAs are single-stranded RNAs and participate in a series of physiological and pathological processes by facilitating post-transcriptional regulation of the target genes [ 76 ]. Numerous abnormally expressing miRNAs are associated with HCC initiation and progression [ 76 , 77 ].…”

“…MicroRNAs are single-stranded RNAs and participate in a series of physiological and pathological processes by facilitating post-transcriptional regulation of the target genes [ 76 ]. Numerous abnormally expressing miRNAs are associated with HCC initiation and progression [ 76 , 77 ]. Various studies have exposed the biological roles of lncRNAs as regulators of transcription, modulators of mRNA processing, and organizers of nuclear domains [ 76 , 77 , 78 , 79 ].…”

“…Numerous abnormally expressing miRNAs are associated with HCC initiation and progression [ 76 , 77 ]. Various studies have exposed the biological roles of lncRNAs as regulators of transcription, modulators of mRNA processing, and organizers of nuclear domains [ 76 , 77 , 78 , 79 ]. Compared with linear RNAs, circRNAs are more stable to exonuclease and ribonuclease, with conserved structure and stable sequence and tissue specificity [ 78 , 79 ].…”

The Biological Roles and Molecular Mechanisms of Long Non-Coding RNA MEG3 in the Hallmarks of Cancer

“…Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs more than 200 nucleotides in length. LncRNAs can act as competing endogenous RNA (ceRNA) that sponges and blocks the effect of miRNAs, a class of ncRNA that suppresses target genes expression at their translational level by binding to their 3′ untranslated regions (3′ UTR) [ 9 ]. Furthermore, lncRNAs could interact with DNA, RNA, protein molecules and/or their complexes, acting as an essential regulator in transcriptional, post-transcriptional, and chromatin remodeling regulations [ 10 ].…”