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.
Highlights
Hepatocellular carcinoma (HCC) is the third cancer-related cause of death worldwide, with chronic hepatitis C virus (HCV) infection as a major risk factor of HCC [1]
Our study revealed that these miRNAs, but not miR-130a, could serve as potential biomarkers for early detection of HCC in high-risk groups, with miR-19a as a biomarker for liver fibrosis progression to cirrhosis to HCC
All HCC patients were on top of HCV cirrhosis and HCC diagnosis was made upon the presence of hepatic focal lesions diagnosed by abdominal ultrasound and confirmed by computed tomography (CT) and/or magnetic resonance imaging according to European Association of the Study of the Liver (EASL) guidelines (2012)
Summary
Hepatocellular carcinoma (HCC) is the third cancer-related cause of death worldwide, with chronic hepatitis C virus (HCV) infection as a major risk factor of HCC [1]. Chronic HCV accounted for 94% of HCC cases in Egypt in 2010, with 6000–7000 deaths/year due to HCC [3]. Prognosis and survival rates are improved significantly with early diagnosis. Current diagnostic methods such as imaging techniques and serological tumor markers, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP, and des-γ-carboxy prothrombin are insufficient for early detection of HCC [4,5]. Circulating miRNAs are deregulated in HCC and are emerging as novel stable and detectable biomarkers for early diagnosis of HCC [9]. Thereby, profiling of circulating HCC-related miRNAs may unravel new molecular biomarkers with high sensitivity and specificity for HCC
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