The Identification and Analysis of MicroRNAs Combined Biomarkers for Hepatocellular Carcinoma Diagnosis

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor with high morbidity and mortality globally. Compared with traditional diagnostic methods, microRNAs (miRNAs) are novel biomarkers with higher accuracy. Objective: We aimed to identify combinatorial biomarkers of miRNAs to construct a classification model for the diagnosis of HCC. Methods: The mature miRNA expression profile data of six cancers (liver, lung, gastric, breast, prostate, and colon) were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database with accession number GSE36915, GSE29250, GSE99417, GSE41970, GSE64333 and GSE35982. The messenger RNA (mRNA) expression profile data of these six cancers were obtained from TCGA. Three R software packages, student’s t-test, and a normalized foldchange method were utilized to identify HCC-specific differentially expressed miRNAs (DEMs). Using all combinations of obtained HCC-specific DEMs as input features, we constructed a classification model by support vector machine searching for the optimal combination. Furthermore, target genes prediction was conducted on the miRWalk 2.0 website to obtain differentially expressed mRNAs (DEmRNAs), and KEGG pathway enrichment was analyzed on the DAVID website. Results: The optimal combination consisted of four miRNAs (hsa-miR-130a-3p, hsa-miR-450b-5p, hsa-miR-136-5p, and hsa-miR-24-1-5p), of which the last one has not been currently reported to be relevant to HCC. The target genes of hsa-miR-24-1-5p (CDC7, ACACA, CTNNA1, and NF2) were involved in the cell cycle, AMPK signaling pathway, Hippo signaling pathway, and insulin signaling pathway, which affect the proliferation, metastasis, and apoptosis of cancer cells. Moreover, the area under the receiver operating characteristic curves of the four miRNAs were all higher than 0.85. Conclusion: These results suggest that the miRNAs combined biomarkers were reliable for the diagnosis of HCC. Hsa-miR-24-1-5p was a novel biomarker for HCC diagnosis identified in this study.