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, 9 (19), 3435-3446
eCollection

A miRNA Combination as Promising Biomarker for Hepatocellular Carcinoma Diagnosis: A Study Based on Bioinformatics Analysis

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A miRNA Combination as Promising Biomarker for Hepatocellular Carcinoma Diagnosis: A Study Based on Bioinformatics Analysis

Jia Ji et al. J Cancer.

Abstract

Background: miRNAs dysregulate in hepatocellular carcinoma (HCC), showing promise for diagnostic biomarkers which may be found through exploration of differentially expressed miRNAs when comparing HCC and normal liver tissues. Materials and Methods: In the present research, candidate miRNAs were selected and verified using screening dataset GSE12717 and training dataset GSE10694, respectively. A miRNA combination was constructed using stepwise logistic regression analysis and validated using two datasets GSE74618 and TCGA. Target genes of miRNAs in the combination were obtained using a miRNA target gene prediction database. Functional analysis was conducted using an online tool DAVID. We also analyzed the mRNA-Seq data of project LIHC from TCGA to identify the hub target genes of the miRNAs. Results: A miRNA combination, which is composed of hsa-miR-221 and hsa-miR-29c was defined in this study. The miRNA combination is more effective in discriminating HCC patients from normal individuals than individual miRNAs. Additionally, the combined miRNAs showed a lower misdiagnosis rate than AFP in HCC diagnosis. In terms of the functional analysis, a total of 27 target genes of hsa-miR-221 and 96 target genes of hsa-miR-29c were obtained. Among which, INSIG1 was the common target of the two miRNAs. It was also found that both previously mentioned miRNAs played important roles in the regulation of transcription, cell proliferation, and involvement in cancer-related pathways. Lastly, 2 hub target genes of hsa-miR-221 and 16 hub target genes of hsa-miR-29c were obtained. Conclusion: We established a miRNA combination as a promising tool for HCC diagnosis, and the target genes we predicted provide possible points of penetration for researching these two miRNAs in HCC.

Keywords: Bioinformatics analysis; Biomarker; Diagnose; Hepatocellular carcinoma; MicroRNA combination; Public gene database.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Overview of the strategy
Figure 2
Figure 2
Microarray assay of miRNAs differentially expressed in the tissues of HCC and normal liver samples. Notes: Heatmap exhibiting the differentially expressed miRNAs in HCC tissues compared to normal liver samples in dataset GSE12717(A) and GSE10694(B). Each column represents an individual sample and each row represents a single miRNA. Expression level of each miRNA in a single sample is depicted according to the color scale. Yellow represents high expression, whereas blue represents low expression. This heatmap was conducted by the “pheatmap” package of R language. p-value<0.05 and |LogFoldChange| >1 were identified as threshold value to judge differentially expressed miRNAs(DEmiRNAs) of GSE12717. adjusted p-value<0.05 and |LogFoldChange| >1 were identified as threshold value to judge differentially expressed miRNAs of GSE10694.
Figure 3
Figure 3
ROC curves to compare the diagnostic accuracy. Notes: ROC plots for the (A) Training set; (B) Validation set GSE74618; (C) Validation set TCGA; (D) microRNA combination in discriminating HCC patients of TNM stage Ⅰ/Ⅱ from the healthy individuals.
Figure 4
Figure 4
Performance of a two-tiered algorithm for HCC diagnosis incorporation the miRNA combination and an AFP cut-off of 20ng/ml.
Figure 5
Figure 5
MiRNA-target gene network. Notes: The circle represents target gene (mRNA), the yellow octagon represents miRNA. Green circles represent the non-hub target genes which have been validated by experimental study. Blue ones represent the hub target genes which have been validated by experimental study. Pink ones represent the hub target genes which haven't been validated by experimental study. The relationship between the miRNA and gene is represented by a grey line. The network was conducted using Cytoscape_3.5.1.

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