Apoptosis is induced by N-myc expression in hepatocytes, a frequent event in hepadnavirus oncogenesis, and is blocked by insulin-like growth factor II.
Induction of hepatocellular carcinoma in woodchucks by woodchuck hepatitis virus is associated with the activation of N-myc gene expression, usually by viral DNA integration in cis to the N-myc locus. We have examined the consequences of N-myc up-regulation in rodent hepatic cells in culture. Mouse alpha ML hepatocytes infected with a retroviral vector overexpressing the woodchuck N-myc2 gene display a higher proliferation rate than parental alpha ML cells but are morphologically unchanged and do not form colonies in soft agar. However, they display an increased propensity to undergo apoptosis, an effect that is markedly augmented by serum deprivation. Expression of the woodchuck hepatitis virus X gene in alpha ML cells does not alter the growth phenotype of the cells and has no effect upon N-myc-dependent apoptosis. However, apoptosis in N-myc2-expressing alpha ML cells is strongly inhibited by insulin-like growth factor II (IGF II). IGF II gene expression is also strongly up-regulated during hepatic carcinogenesis in vivo in virally infected animals and has been speculated to be part of an autocrine growth-stimulatory pathway. Our results suggest that IGF II may play another role in the development of virus-induced hepatoma: the prevention of programmed cell death triggered by deregulated N-myc expression.
Ueda
K
K
Howard Hughes Medical Institute, University of California Medical Center, San Francisco 94143-0414, USA.
Ganem
D
D
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D015870:Gene Expression; D016259:Genes, myc / Q000502:physiology; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000502:physiology*; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008392:Marmota; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D014764:Viral Proteins; C090237:protein X, Woodchuck hepatitis B virus; D007335:Insulin-Like Growth Factor II