Terradillos O, Billet O, Renard C A, Levy R, Molina T, Briand P, Buendia M A
Unité de Recombinaison et Expression Génétique (INSERM U163), Institut Pasteur, Paris, France.
Oncogene. 1997 Jan 30;14(4):395-404. doi: 10.1038/sj.onc.1200850.
The hepatitis B virus X protein (HBx) is thought to be implicated in the development of hepatocellular carcinoma, but its exact function remains controversial. Transgenic mice from PEX7 and AX16 lineages that express HBx in the liver under control of different viral regulatory elements develop no liver pathology (Billet et al., 1995). We have crossed these two mouse lineages with WHV/c-myc oncomice in which liver-specific expression of c-myc driven by woodchuck hepatitis virus (WHV) regulatory sequences causes liver cancer in all animals. The average tumor latency was shortened by 2 to 3 months in bitransgenic animals from all populations compared with simple c-myc transgenic littermates. At preneoplastic stages, adult bitransgenic mice showed four to fivefold enhanced expression of the c-myc transgene, increased hepatocyte proliferation and more extensive liver lesions compared with simple WHV/c-myc transgenics. Thus in this model, HBx alone has no direct pathological effect but it is shown to accelerate tumor development induced by c-myc. The data presented here firmly establish the oncogenic potential of HBx, apparently acting as a tumor promoter. This model offers unique opportunities to investigate the mechanisms by which HBx trans-activates the expression of target genes and deregulates the hepatocyte growth control in vivo.
乙型肝炎病毒X蛋白（HBx）被认为与肝细胞癌的发生有关，但其确切功能仍存在争议。来自PEX7和AX16谱系的转基因小鼠在不同病毒调控元件的控制下在肝脏中表达HBx，但未出现肝脏病理变化（Billet等人，1995年）。我们已将这两个小鼠谱系与携带土拨鼠肝炎病毒（WHV）调控序列驱动的c-myc肝脏特异性表达的WHV/c-myc致癌小鼠进行杂交，该表达会导致所有动物患肝癌。与单纯的c-myc转基因同窝小鼠相比，所有群体的双转基因动物平均肿瘤潜伏期缩短了2至3个月。在肿瘤发生前阶段，与单纯的WHV/c-myc转基因小鼠相比，成年双转基因小鼠显示c-myc转基因表达增强了四到五倍，肝细胞增殖增加且肝脏病变更广泛。因此，在这个模型中，单独的HBx没有直接的病理作用，但它被证明会加速由c-myc诱导的肿瘤发展。此处呈现的数据有力地证实了HBx的致癌潜力，其显然作为一种肿瘤促进剂发挥作用。该模型为研究HBx在体内反式激活靶基因表达并解除肝细胞生长控制的机制提供了独特机会。
