Etiemble J, Degott C, Renard C A, Fourel G, Shamoon B, Vitvitski-Trépo L, Hsu T Y, Tiollais P, Babinet C, Buendia M A
Unité de Recombinaison et Expression Génétique (Inserm U163, Paris, France.
Oncogene. 1994 Mar;9(3):727-37.
The high oncogenic efficiency of woodchuck hepatitis virus (WHV) has been correlated with the ability of this virus to provoke insertional activation of myc family genes. To assess the impact of viral integration on liver cell transformation, we have generated transgenic mice carrying the mutated c-myc gene and adjacent viral DNA from a woodchuck tumor, in original configuration. Virtually all mice from two different strains developed hepatocellular carcinoma with a mean latency period of 8-12 months. The c-myc transgene was expressed transiently in neonatal livers, and re-expressed at preneoplastic and neoplastic stages in adult livers. Woodchuck c-myc mRNA driven by the normal P1 and P2 promoters and WHV-specific transcripts encoding viral surface antigens were produced in a strictly co-regulated fashion during development and tumorigenesis, indicating a predominant regulatory influence of the viral enhancer. Furthermore, the activity of the viral enhancer in response to various biological stimuli was apparently modulated by glucose uptake and glucagon/insulin balance in differentiated hepatocytes. In this model, a viral integration event selected from a naturally occurring tumor proved to be determinant for induction of hepatocarcinogenesis, although enforced, liver-specific expression of c-myc was limited to a particular developmental stage.
土拨鼠肝炎病毒（WHV）的高致癌效率与该病毒激发myc家族基因插入激活的能力相关。为了评估病毒整合对肝细胞转化的影响，我们构建了转基因小鼠，其携带来自土拨鼠肿瘤的突变c-myc基因及相邻病毒DNA，保持原始构型。来自两个不同品系的几乎所有小鼠都发展出肝细胞癌，平均潜伏期为8至12个月。c-myc转基因在新生肝脏中短暂表达，并在成年肝脏的癌前和肿瘤阶段重新表达。在发育和肿瘤发生过程中，由正常P1和P2启动子驱动的土拨鼠c-myc mRNA以及编码病毒表面抗原的WHV特异性转录本以严格共调控的方式产生，表明病毒增强子具有主要的调控影响。此外，在分化的肝细胞中，病毒增强子对各种生物刺激的反应活性显然受到葡萄糖摄取和胰高血糖素/胰岛素平衡的调节。在这个模型中，从自然发生的肿瘤中选择的一个病毒整合事件被证明是诱导肝癌发生的决定性因素，尽管强制的肝脏特异性c-myc表达仅限于特定的发育阶段。
