Abstract
The intronless N-myc2 gene was originally identified as the major target of hepatitis virus insertion in woodchuck liver tumors. Here we report that transgenic mice carrying the N-myc2 gene controlled by woodchuck hepatitis virus (WHV) regulatory sequences are highly predisposed to liver cancer. In a WHV/N-myc2 transgenic line, hepatocellular carcinomas or adenomas arose in over 70% of mice, despite barely detectable expression of the methylated transgene in liver cells. Furthermore, a transgenic founder carrying unmethylated transgene sequences succumbed to a large liver tumor by the age of two months, demonstrating the high oncogenicity of the woodchuck N-myc2 retroposon. Stabilizing mutations or deletions of β-catenin were found in 25% of liver tumors and correlated with reduced tumor latency (P<0.05), confirming the important role of β-catenin activation in Myc-induced tumorigenesis. The ability of the tumor suppressor gene p53 to cooperate with N-myc2 in liver cell transformation was tested by introducing a p53-null allele into WHV/N-myc2 transgenic mice. The loss of one p53 allele in transgenic animals markedly accelerated the onset of liver cancer (P=0.0001), and most tumors of WHV/N-myc2 p53+/Δ mice harbored either a deletion of the wt p53 allele or a β-catenin mutation. These findings provide direct evidence that activation of N-myc2 and reduction of p53 levels act synergistically during multistage carcinogenesis in vivo and suggest that different genetic pathways may underlie liver carcinogenesis initiated by a myc transgene.
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Acknowledgements
We are grateful to C Babinet for generating the WHV/N-myc2 transgenic mice. T Jacks provided the P53 knock-out mice and the Centre de Développement des Techniques Avancées pour l'Expérimentation Animale (CNRS, Orléans, France) provided pathogen-free animals on C57/Bl6 background. We thank O Terradillos for help in immunofluorescence studies and J Tran van Nhieu for immunohistological analysis. This work was supported in part by the Association pour la Recherche sur le Cancer (ARC contract 5236). MA Buendia is an agent of the Centre National pour la Recherche Scientifique, France.
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Renard, CA., Fourel, G., Bralet, MP. et al. Hepatocellular carcinoma in WHV/N-myc2 transgenic mice: oncogenic mutations of β-catenin and synergistic effect of p53 null alleles. Oncogene 19, 2678–2686 (2000). https://doi.org/10.1038/sj.onc.1203617
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DOI: https://doi.org/10.1038/sj.onc.1203617
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