Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis
Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis
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DOI：
10.1038/sj.onc.1208628
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发表时间：
2005-06-01
期刊：
影响因子：
8
通讯作者：
Okanoue, T
中科院分区：
文献类型：
--
作者：
Minami, M;Daimon, Y;Okanoue, T
越来越多的证据表明，乙肝病毒的整合和由此产生的插入突变在肝细胞癌的细胞生长或维持中起着重要的作用。为了确定在感染的这一阶段是否会发生并影响细胞基因，我们使用针对人类Alu-Repeat和乙肝病毒的特异性引物进行了PCR扩增，分析了无肝细胞癌的慢性肝炎组织中的病毒-宿主连接。我们从6名患者身上获得了42个独立的病毒-宿主连接，并确定了42个连接中的20个的染色体位置。在六个克隆中，每个整合明显影响一个基因。这六个候选基因包括一个已知的肿瘤抑制基因，三个对器官发育至关重要的果蝇基因的人类同源物，一个可能的癌基因和一个最近发现的趋化因子。我们的数据与先前报道的肝细胞癌中的乙肝病毒整合子一起表明，乙肝病毒优先整合到3号染色体(P=0.022)。我们的病毒标记方法提供了(A)在慢性感染的早期阶段乙肝病毒在肝细胞中整合的确凿证据，(B)揭示了可能受乙肝病毒整合影响的细胞基因，并可能参与导致癌症发生的早期步骤。
Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). To determine if HBV integration occurs and affects cellular genes at such a stage of infection, we analysed viral-host junctions in chronic hepatitis tissues without HCC using PCR amplification with primers specific to human Alu-repeat and HBV. We obtained 42 independent viral-host junctions from six patients examined and identified chromosomal locations for 20 of the 42 junctions. In six clones, each integration apparently affected a single gene. These six candidate genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. Our data, together with previously reported HBV integrants in HCCs, suggested preferential HBV integration into chromosome 3 (P = 0.022). Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and potentially involved in early steps of the process leading to carcinogenesis.