Construction of a disease-specific lncRNA-miRNA-mRNA regulatory network reveals potential regulatory axes and prognostic biomarkers for hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with a high incidence and poor prognosis. Exploration of the underlying mechanisms and effective prognostic indicators is conducive to clinical management and optimization of treatment. The RNA‐seq and clinical phenotype data of HCC were retrieved from The Cancer Genome Atlas (TCGA), and differential expression analysis was performed. Then, a differential lncRNA‐miRNA‐mRNA regulatory network was constructed, and the key genes were further identified and validated. By integrating this network with the online tool‐based ceRNA network, an HCC‐specific ceRNA network was obtained, and lncRNA‐miRNA‐mRNA regulatory axes were extracted. RNAs associated with prognosis were further obtained, and multivariate Cox regression models were established to identify the prognostic signature and nomogram. As a result, 198 DElncRNAs, 120 DEmiRNAs, and 2827 DEmRNAs were identified, and 30 key genes identified from the differential network were enriched in four cancer‐related pathways. Four HCC‐specific lncRNA‐miRNA‐mRNA regulatory axes were extracted, and SNHG11, CRNDE, MYLK‐AS1, E2F3, and CHEK1 were found to be related with HCC prognosis. Multivariate Cox regression analysis identified a prognostic signature, comprised of CRNDE, MYLK‐AS1, and CHEK1, for overall survival (OS) of HCC. A nomogram comprising the prognostic signature and pathological stage was established and showed some net clinical benefits. The AUC of the prognostic signature and nomogram for 1‐year, 3‐year, and 5‐year survival was 0.777 (0.657‐0.865), 0.722 (0.640‐0.848), and 0.630 (0.528‐0.823), and 0.751 (0.664‐0.870), 0.773 (0.707‐0.849), and 0.734 (0.638‐0.845), respectively. These results provided clues for the study of potential biomarkers and therapeutic targets for HCC. In addition, the obtained 30 key genes and 4 regulatory axes might also help elucidate the underlying mechanism of HCC.