Terris B, Marchio A, Mattei M G, Fagan E, Lok A, Tiollais P, Dejean A
Unité de Recombinaison et Expression Génétique (INSERM U 163, CNRS URA 217), Institut Pasteur, Paris.
Gastroenterol Clin Biol. 1992;16(6-7):511-7.
Although epidemiologic studies have clearly demonstrated the importance of the hepatitis B virus in the genesis of hepatocellular carcinoma, the molecular basis for this tumorigenic effect is still under debate. The finding of hepatitis B virus DNA integration into human liver DNA in many cases of hepatocellular carcinoma suggested that these integrated viral sequences may be involved in liver carcinogenesis. In an attempt to clarify this point, we studied 9 tumors which developed in non cirrhotic livers. All tumors contained viral integrations (ranging from 1 to 6 different integrants) and 4 showed abnormal hepatitis B virus mRNA (2.3 to 7.5 kilobases long). The analysis of the corresponding cDNAs revealed the existence of hybrid transcripts containing both genomic and viral sequences. In 2 cases, the viral-host junctions were mapped within the cohesive-end region of the hepatitis B virus genome leading to the production of a transcript encoding a 3' truncated X protein. In another case, the cellular sequences present in the co-transcript were located in 5' with respect to the hepatitis B virus sequences. This observation strongly suggests that, in this patient, integration took place near a cellular gene. Further analysis of this integrant should help in identifying the putative gene and its application in the development of the tumor. We conclude that the study of abnormal hepatitis B virus transcripts in liver tumors provides a positive approach to study the direct role of HBV in carcinogenesis as an insertional mutagen.
尽管流行病学研究已明确证明乙型肝炎病毒在肝细胞癌发生过程中的重要性，但这种致瘤作用的分子基础仍存在争议。在许多肝细胞癌病例中发现乙型肝炎病毒DNA整合到人类肝脏DNA中，这表明这些整合的病毒序列可能参与肝脏致癌过程。为了阐明这一点，我们研究了9例在非肝硬化肝脏中发生的肿瘤。所有肿瘤均含有病毒整合（1至6种不同的整合体），4例显示异常的乙型肝炎病毒mRNA（长度为2.3至7.5千碱基）。对相应cDNA的分析揭示了存在同时包含基因组和病毒序列的杂交转录本。在2例中，病毒-宿主连接位点定位于乙型肝炎病毒基因组的粘性末端区域内，导致产生编码3'截短X蛋白的转录本。在另一例中，共转录本中存在的细胞序列相对于乙型肝炎病毒序列位于5'端。这一观察结果强烈表明，在该患者中，整合发生在一个细胞基因附近。对该整合体的进一步分析应有助于鉴定推定的基因及其在肿瘤发生中的作用。我们得出结论，研究肝脏肿瘤中异常乙型肝炎病毒转录本为研究HBV作为插入诱变剂在致癌作用中的直接作用提供了一种积极的方法。
