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. 2015 Sep 9;10(9):e0137706.
doi: 10.1371/journal.pone.0137706. eCollection 2015.

Serum MicroRNAs as Potential Biomarkers for Early Diagnosis of Hepatitis C Virus-Related Hepatocellular Carcinoma in Egyptian Patients

Tarek K Motawi  1 , Olfat G Shaker  2 , Shohda A El-Maraghy  1 , Mahmoud A Senousy  1
Affiliations

Serum MicroRNAs as Potential Biomarkers for Early Diagnosis of Hepatitis C Virus-Related Hepatocellular Carcinoma in Egyptian Patients

Tarek K Motawi et al. PLoS One. .

Abstract

Circulating microRNAs are deregulated in liver fibrosis and hepatocellular carcinoma (HCC) and are candidate biomarkers. This study investigated the potential of serum microRNAs; miR-19a, miR-296, miR-130a, miR-195, miR-192, miR-34a, and miR-146a as early diagnostic biomarkers for hepatitis C virus (HCV)-related HCC. As how these microRNAs change during liver fibrosis progression is not clear, we explored their serum levels during fibrosis progression in HCV-associated chronic liver disease (CLD) and if they could serve as non-invasive biomarkers for fibrosis progression to HCC. 112 Egyptian HCV-HCC patients, 125 non-malignant HCV-CLD patients, and 42 healthy controls were included. CLD patients were subdivided according to Metavir fibrosis-scoring. Serum microRNAs were measured by qRT-PCR custom array. Serum microRNAs were deregulated in HCC versus controls, and except miR-130a, they were differentially expressed between HCC and CLD or late fibrosis (F3-F4) subgroup. Serum microRNAs were not significantly different between individual fibrosis-stages or between F1-F2 (early/moderate fibrosis) and F3-F4. Only miR-19a was significantly downregulated from liver fibrosis (F1-F3) to cirrhosis (F4) to HCC. Individual microRNAs discriminated HCC from controls, and except miR-130a, they distinguished HCC from CLD or F3-F4 patients by receiver-operating-characteristic analysis. Multivariate logistic analysis revealed a panel of four microRNAs (miR-19a, miR-195, miR-192, and miR-146a) with high diagnostic accuracy for HCC (AUC = 0.946). The microRNA panel also discriminated HCC from controls (AUC = 0.949), CLD (AUC = 0.945), and F3-F4 (AUC = 0.955). Studied microRNAs were positively correlated in HCC group. miR-19a and miR-34a were correlated with portal vein thrombosis and HCC staging scores, respectively. In conclusion, studied microRNAs, but not miR-130a, could serve as potential early biomarkers for HCC in high-risk groups, with miR-19a as a biomarker for liver fibrosis progression to cirrhosis to HCC. We identified a panel of four serum microRNAs with high accuracy in HCC diagnosis. Additional studies are required to confirm this panel and test its prognostic significance.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Differential expression of serum miRNA levels in HCC and healthy controls.
Relative expression of miRNAs miR-19a (P = 0.0002), miR-296 (P<0.0001), miR-130a (P<0.0001), miR-195 (P = 0.04), miR-192 (P<0.0001), miR-34a (P<0.0001), and miR-146a (P<0.0001) in serum of HCC (n = 112) compared to healthy controls (n = 42). Data are presented as median with interquartile range. Data were analyzed by Mann-Whitney U-test.* means statistical significance (P<0.05).
Fig 2
Fig 2. Differential expression of serum miRNA levels in HCC and CLD patients.
The box represents the 25%-75% percentiles; the line inside the box represents the median and the upper and lower lines representing the 10%-90% percentiles of fold change in expression levels of studied miRNAs in serum of CLD (n = 125) and HCC patients (n = 112). Data were analyzed by Mann-Whitney U-test.
Fig 3
Fig 3. Signature of serum miRNAs relative expression during HCV-related liver disease progression.
Panel (A) represents fold change of miRNA expression levels in early fibrosis (F1-F2, n = 75), late fibrosis (F3-F4, n = 50), and HCC (n = 112) groups. Comparison between F1-F2 vs F3-F4 or F3-F4 vs HCC was analyzed by Mann-Whitney U-test. Panel (B) represents detailed analysis of miRNA relative expression levels at different fibrosis stages (F1, n = 45, F2, n = 30, F3, n = 18, F4, n = 32) and HCC (n = 112). Comparison was done by Kruskal-Wallis test. Mann-Whitney U-test was used to compare F1-F3 vs F4 or F4 vs HCC. The box represents the 25%-75% percentiles; the line inside the box represents the median and the upper and lower lines representing the 10%-90% percentiles.
Fig 4
Fig 4. Serum miRNAs as diagnostic biomarkers to differentiate HCC patients from healthy controls.
ROC curve analysis of serum miRNAs as diagnostic biomarkers differentiating HCC patients (n = 112) from healthy controls (n = 42).
Fig 5
Fig 5. Serum miRNAs as diagnostic biomarkers to differentiate HCC from non-malignant CLD.
ROC curve analysis of serum miRNAs as diagnostic biomarkers differentiating HCC patients (n = 112) from CLD (n = 125).
Fig 6
Fig 6. Serum miRNAs as diagnostic biomarkers to differentiate HCC patients from late fibrosis (F3-F4) subgroup.
ROC curve analysis of serum miRNAs as diagnostic biomarkers differentiating HCC (n = 112) from F3-F4 patients (n = 50).
Fig 7
Fig 7. Diagnostic performance of the miRNA panel.
AUCs of the miRNA panel (A) and miRNA panel in differentiating HCC from healthy controls (B), CLD (C), and F3-F4 patients (D).
Fig 8
Fig 8. Comparison of AUC of the miRNA panel with that of AFP.
AUCs of the miRNA panel and AFP in differentiating HCC from healthy controls (A), CLD (B), and F3-F4 patients (C).
Fig 9
Fig 9. Correlations between serum miRNAs levels in HCC group.
A correlation map with a blue-red (cold-hot) scale. The blue color corresponds to a correlation close to -1 and the red color corresponds to a correlation close to 1. Green corresponds to a correlation close to 0. Correlations are made by spearman correlation.
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Grants and funding

This research was supported by the Research Service of the Faculty of Pharmacy, Cairo University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.