Identification of miRNAs, mRNAs, lncRNAs, and circRNAs associated with hepatocellular carcinoma recurrence after interferon treatment

AbstractObjective: Interferons have shown varied sensitivity in the treatment of hepatocellular carcinoma (HCC). Here, we studied the molecular mechanism of an interferon to explore its specific targets in the anti-HCC metastasis process and the biomarkers that can effectively predict its clinical efficacy. Methods: Differentially expressed (DE)-miRNAs, -mRNAs, -lncRNAs, and -circRNAs were screened from 15 HCC patients: five patients had received no postoperative interferon-alpha treatment (control) and 10 patients had been injected with interferon-alpha postoperatively. Tumor recurrence and metastasis occurred in five of the ten patients who had received postoperative treatment (case2), while no such symptoms occurred in the five other patients (case1). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to determine the principal functions of the differentially expressed genes. Analyses of the networks of protein-protein interactions (PPI) and competing endogenous RNA (ceRNA) were also performed. In addition, a series-cluster analysis was performed to analyze changes in gene expression across different stages of HCC. Results: A total of 36 union miRNAs (11 up-regulated, 25 down-regulated), 175 union mRNAs (94 up-regulated, 81 down-regulated), 65 union lncRNAs (9 up-regulated, 56 down-regulated), and 52 union circRNAs (30 up-regulated, 22 down-regulated) were obtained between the control vs case1 and case2 vs case1 groups. DE-mRNAs were mainly enriched in the mitochondrial inner membrane, endocytic vesicle membrane, regulation of transcription, and DNA-templated synthesis. DE-circRNAs were mainly enriched in the Golgi apparatus, unfolded protein binding, and membrane, clathrin-coated vesicles, and endocytic recycling. The proteins that had the 11 highest values of degree were CD19, SRC, CD22, CD68, CXCL10, PAX5, BLK, CD1D, CXCR5, MS4A1, and TYMS. The integrated ceRNA network contained 162 nodes, which included 68 DE-mRNAs, 26 DE-miRNAs, 45 DE-lncRNAs, and 23 DE-circRNAs. A total of 4 DE-miRNAs, 175 DE-mRNAs, 65 DE-lncRNAs, and 52 DE-circRNAs were classified into eight profiles, respectively. Conclusion: We screened a number of mRNAs, miRNAs, lncRNAs, and circRNAs that might be the target of interferon-alpha therapy for HCC. The results may lay a foundation for investigating the different sensitivities of interferon-alpha in the treatment of HCC.