Murakami Y, Saigo K, Takashima H, Minami M, Okanoue T, Bréchot C, Paterlini-Bréchot P
Department of Gastroenterology, Fukui National Hospital, 33-1 Sakuragaoka, Tsuruga, Fukui 914-0195, Japan.
Gut. 2005 Aug;54(8):1162-8. doi: 10.1136/gut.2004.054452.
Hepatitis B virus (HBV) DNA integration into or close to cellular genes is frequently detected in HBV positive hepatocellular carcinomas (HCC). We have previously shown that viral integration can lead to aberrant target gene transcription. In this study, we attempted to investigate common pathways to hepatocarcinogenesis.
By using a modified Alu-polymerase chain reaction approach, we analysed 50 HCCs along with 10 previously published cases.
Sixty eight cellular flanking sequences (seven repetitive or unidentified sequences, 42 cellular genes, and 19 sequences potentially coding for unknown proteins) were obtained. Fifteen cancer related genes and 25 cellular genes were identified. HBV integration recurrently targeted the human telomerase reverse transcriptase gene (three cases) and genes belonging to distinct pathways: calcium signalling related genes, 60s ribosomal protein encoding genes, and platelet derived growth factor and mixed lineage leukaemia encoding genes. Two tumour suppressor genes and five genes involved in the control of apoptosis were also found at the integration site. The viral insertion site was distributed over all chromosomes except 13, X, and Y.
In 61/68 (89.7%) cases, HBV DNA was integrated into cellular genes potentially providing cell growth advantage. Identification of recurrent viral integration sites into genes of the same family allows recognition of common cell signalling pathways activated in hepatocarcinogenesis.
在乙肝病毒（HBV）阳性的肝细胞癌（HCC）中，经常检测到HBV DNA整合到细胞基因内部或其附近。我们之前已经表明，病毒整合可导致靶标基因转录异常。在本研究中，我们试图探究肝癌发生的常见途径。
通过使用改良的Alu聚合酶链反应方法，我们分析了50例肝细胞癌以及10例先前发表的病例。
获得了68个细胞侧翼序列（7个重复或未鉴定序列、42个细胞基因以及19个可能编码未知蛋白质的序列）。鉴定出15个癌症相关基因和25个细胞基因。HBV整合经常靶向人类端粒酶逆转录酶基因（3例）以及属于不同途径的基因：钙信号相关基因、60S核糖体蛋白编码基因、血小板衍生生长因子和混合谱系白血病编码基因。在整合位点还发现了两个肿瘤抑制基因和五个参与细胞凋亡调控的基因。病毒插入位点分布在除13号、X和Y染色体之外的所有染色体上。
在61/68（89.7%）的病例中，HBV DNA整合到可能提供细胞生长优势的细胞基因中。鉴定出病毒在同一家族基因中的重复整合位点，有助于识别在肝癌发生过程中被激活的常见细胞信号通路。
