Uncovering the potential differentially expressed miRNAs as diagnostic biomarkers for hepatocellular carcinoma based on machine learning in The Cancer Genome Atlas database.

ABSTRACT

The present study aimed to identify novel diagnostic differentially expressed microRNAs (miRNAs/miRs) in order to understand the molecular mechanisms underlying hepatocellular carcinoma. The expression data of miRNA and mRNA were downloaded for differential expression analysis. Optimal diagnostic differentially expressed miRNA biomarkers were identified via a random forest algorithm. Classification models were established to distinguish patients with hepatocellular carcinoma and normal individuals. A regulatory network between optimal diagnostic differentially expressed miRNA and differentially expressed mRNAs was then constructed. The GSE63046 dataset and in vitro experiments were used to validate the expression of the optimal diagnostic differentially expressed miRNAs identified. In addition, diagnostic and prognostic analyses of optimal diagnostic differentially expressed miRNAs were performed. In total, 14 differentially expressed miRNAs (all upregulated) and 2,982 differentially expressed mRNAs (1,989 upregulated and 993 downregulated) were identified. hsa­miR­10b­5p, hsa­miR­10b­3p, hsa­miR­224­5p, hsa­miR­183­5p and hsa­miR­182­5p were considered as the optimal diagnostic biomarkers for hepatocellular carcinoma. The mRNAs targeted by these five miRNAs included secreted frizzled related protein 1 (SFRP1), endothelin receptor type B (EDNRB), nuclear receptor subfamily 4 group A member 3 (NR4A3), four and a half LIM domains 2 (FHL2), NK3 homeobox 1 (NKX3­1), interleukin 6 signal transducer (IL6ST) and forkhead box O1 (FOXO1). 'Bile acid biosynthesis and cholesterol' was the most enriched signaling pathways of these target mRNAs. The expression validation of the five miRNAs was consistent with the present bioinformatics analysis. Notably, hsa­miR­10b­5p and hsa­miR­10b­3p had a significant prognosis value for patients with hepatocellular carcinoma. In conclusion, the five differentially expressed miRNAs may be considered as diagnostic biomarkers for patients with hepatocellular carcinoma. In addition, the differential expression levels of the targets of these five mRNAs, including SFRP1, EDNRB, NR4A3, FHL2, NKX3­1, IL6ST and FOXO1, may be involved in hepatocellular carcinoma tumorigenesis.