Serum microRNA Profiles Serve as Novel Biomarkers for HBV Infection and Diagnosis of HBV-Positive Hepatocarcinoma
Serum microRNA Profiles Serve as Novel Biomarkers for HBV Infection and Diagnosis of HBV-Positive Hepatocarcinoma
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血清 microRNA 谱可作为 HBV 感染和诊断 HBV 阳性肝癌的新型生物标志物。
DOI：
10.1158/0008-5472.can-10-1001
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Zen, Ke
中科院分区：
文献类型：
--
作者：
Li, Li-Min;Hu, Zhi-Bin;Zen, Ke
由于缺乏生物标志物，诊断乙肝病毒阳性的肝细胞癌，特别是不依赖于肝硬变病因的肝细胞癌，是一个巨大的挑战。在这里，我们检验了一种假设，即血清中microRNAs(MiRNAs)的表达谱可以作为诊断乙肝病毒感染和乙肝病毒阳性肝细胞癌的生物标志物。我们招募了513名受试者(210名对照组、135名乙肝病毒携带者、48名丙型肝炎病毒携带者和120名肝癌患者)，采用了Solexa测序的初步筛选策略，然后用基于TaqMan探针的定量逆转录-聚合酶链式反应进行验证。首先，由于慢性乙型病毒性肝炎与肝细胞癌的关系密切，我们比较了乙肝病毒血清和对照血清中miRNA的表达谱，成功地获得了13个在乙肝病毒血清中差异表达的miRNA。这种基于13-miRNA的生物标记物不仅可以准确地区分乙肝患者和对照组和丙型肝炎患者，还可以区分乙肝病毒阳性的肝细胞癌患者和对照组和乙肝患者。其次，我们直接比较了肝癌血清和对照组的miRNA表达，发现了6个在肝癌样本中显著上调的miRNAs。有趣的是，其中两个miRNAs，miR-375和miR-92a，也被我们的第一种方法鉴定为乙肝病毒特异性的。当我们使用其中3个miRNAs(miR-25、miR-375和let-7f)作为生物标志物时，我们可以清楚地将肝癌病例与对照区分开来，仅miR-375在预测肝癌方面的ROC为0.96(特异性：96%；敏感性：100%)。总之，我们的研究首次证明，血清miRNA图谱可以作为新的、非侵入性的生物标志物用于乙肝病毒感染和乙肝病毒阳性肝细胞癌的诊断。
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.