Serum microRNA Profiles Serve as Novel Biomarkers for HBV Infection and Diagnosis of HBV-Positive Hepatocarcinoma

Abstract

Diagnosis of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), particularly HCC independent of cirrhosis etiology, presents a great challenge because of a lack of biomarkers. Here we test the hypothesis that expression profiles of microRNAs (miRNAs) in serum can serve as biomarkers for diagnosis of HBV infection and HBV-positive HCC. We recruited 513 subjects (210 controls and 135 HBV-, 48 hepatitis C virus (HCV)-, and 120 HCC-affected individuals) and employed a strategy of initial screening by Solexa sequencing followed by validation with TaqMan probe-based quantitative reverse transcription-PCR assay. First, because of a close link between chronic hepatitis B and HCC, we compared miRNA expression profiles in HBV serum with that in control serum and successfully obtained 13 miRNAs that were differentially expressed in HBV serum. This 13-miRNA-based biomarker accurately discriminated not only HBV cases from controls and HCV cases, but also HBV-positive HCC cases from control and HBV cases. Second, we directly compared miRNA expressions in HCC serum with those in controls and identified 6 miRNAs that were significantly upregulated in HCC samples. Interestingly, 2 of these miRNAs, miR-375 and miR-92a, were also identified by our first approach as HBV specific. When we employed 3 of these miRNAs (miR-25, miR-375, and let-7f) as biomarkers, we could clearly separate HCC cases from controls, and miR-375 alone had an ROC of 0.96 (specificity: 96%; sensitivity: 100%) in HCC prediction. In conclusion, our study demonstrates for the first time that serum miRNA profiles can serve as novel and noninvasive biomarkers for HBV infection and HBV-positive HCC diagnosis. Cancer Res; 70(23); 9798-807. Ó2010 AACR.

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“…Specific serum miRNA expression profiles show a great potential to serve as a novel class of biomarkers for the diagnosis of cancer and other diseases [5,6]. Numerous reports have subsequently shown that unique expression patterns of circulating miRNAs reflect various physiological and pathological conditions [7][8][9][10][11][12].…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…However, after surgical resection, it tends to decrease in the tissue and to increase in the plasma, thus indicating a prognostic role. Conversely, other studies demonstrated that miR-92a is up-regulated in serum of patients with HBV-positive HCC compared to control groups (Li et al, 2010a;Giray et al, 2014).…”

“…Also, miR-375 seems to be the only one which allows to specifically differentiate HBV-related HCC patients from HCC patients without HBV. It has been reported an AUC of ROC curve equal to 0.96 and a sensitivity and specificity of 96% and 100%, respectively (Li et al, 2011b). Recent data suggested that circulating miR-375 could be a novel potential predictive biomarker in early-stage HCC (Yin et al, 2015).…”

MicroRNAs in Liver Disease: Bench to Bedside

“…40,44,45 Serum/plasma levels of miR-122 correlate with hepatic necro-inflammation, liver damage, cell death and increased aminotransferase levels in acute and chronic liver diseases. 44,[46][47][48][49] Interestingly, hepatic and circulating miR-122 levels do not correlate in NAFLD 14,39,[50][51][52][53][54][55] or viral hepatitis 41,47,49,56 although both have been statistically associated with various measures of disease severity in these studies. Together these studies show that miR-122 may play a role in most liver diseases.…”

“…A recent report demonstrated the potential of a plasma miR panel (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-801) to identify HBV related HCC, 68 while a spate study found that levels of miR-25, miR-375, and let-7f are increased in the circulation of patients with HBV associated HCC. 56 Together these studies highlight the diverse roles that miRs play in the cellular response to CHB.…”