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Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

Oncogene volume 22, pages 2762–2771 (2003)Cite this article

Abstract

The role of interferon-α (IFN-α) 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-α 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-α 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-α 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-α in human cirrhotic livers showing c-myc upregulation.

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Abbreviations

IFN-α:

interferon-alpha

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

HCC:

hepatocellular carcinoma

mTERT:

catalytic subunit of mouse telomerase

PCNA:

Proliferating cell nuclear antigen

PCR:

Polymerase chain reaction

RT–PCR:

reverse transcription-PCR

TRAP:

telomeric repeat amplification protocol

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Acknowledgements

We thank Dr Marie-Annick Buendia for her kind gift of X/myc bitransgenic mice, and Schering-Plough Laboratories for providing human recombinant IFN-α hybrid B/D and support.

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Authors and Affiliations

  1. INSERM U271, Virus des Hépatites et Pathologies Associées, 151 Cours Albert Thomas, Lyon, 69424, Cedex 03, France

    Philippe Merle, Luc Barraud, Lydie Lefrançois, Mireille Maisonnas, Isabelle Bordes, Isabelle Savre-Train, Christian Trepo & Ludmila Vitvitski-Trepo

  2. Département d'Anatomie Pathologique, Laboratoires Marcel-Mérieux, Avenue Tony Garnier, Lyon, 69365, Cedex 07, France

    Michele Chevallier & Sylviane Guerret

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  1. Philippe Merle
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Correspondence to Christian Trepo.

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Merle, P., Barraud, L., Lefrançois, L. et al. Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice. Oncogene 22, 2762–2771 (2003). https://doi.org/10.1038/sj.onc.1206375

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