Long-term high-dose interferon-alpha therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice.
The role of interferon-alpha (IFN-alpha) remains unclear in prevention of virus-induced hepatocellular carcinoma in humans. We have investigated it herewith in the X/myc transgenic mouse model of Hepadnavirus-related hepatocarcinogenesis because of upregulation of c-myc oncogene in the liver. We have demonstrated that IFN-alpha can downregulate dose-dependently hepatocyte proliferation and c-myc overexpression at early premalignant stages, while it does not affect either hepatocyte apoptosis or telomerase activity at these steps. However, continuous and long-term administration of IFN-alpha dose-dependently delays tumor onset in dysplastic livers and increases overall survival of animals, more efficiently whether started before the onset of dysplasia. The present study therefore highlights that early preventive administration of IFN-alpha can slow down evolution towards hepatocellular carcinoma via repression of c-myc and hepatocyte proliferation at premalignant steps in experimental c-myc-induced hepatocarcinogenesis. However, the transient effect observed in this study emphasizes a need to clarify the possible mechanisms of acquired resistance and subsequent therapeutic escape. Our experimental model may be a pertinent tool to explore antioncogenic properties of IFN-alpha in human cirrhotic livers showing c-myc upregulation.
INSERM U271, Virus des Hépatites et Pathologies Associées, 151 Cours Albert Thomas, 69424 Lyon Cedex 03, France.
Philippe
P
Merle
Luc
L
Barraud
Lydie
L
Lefrançois
Michele
M
Chevallier
Sylviane
S
Guerret
Mireille
M
Maisonnas
Isabelle
I
Bordes
Isabelle
I
Savre-Train
Christian
C
Trepo
Ludmila
L
Vitvitski-Trepo
D000818:Animals; D000998:Antiviral Agents; D017209:Apoptosis; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000517:prevention & control* / Q000821:virology*; D017931:DNA Primers; D005260:Female; D016259:Genes, myc; D015613:Hepadnaviridae / Q000302:isolation & purification; D018347:Hepadnaviridae Infections / Q000150:complications* / Q000517:prevention & control; D022781:Hepatocytes / Q000473:pathology; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000517:prevention & control* / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000998:Antiviral Agents; D017931:DNA Primers; D016898:Interferon-alpha