Preliminary results of interferon-alpha therapy on woodchuck hepatitis virus-induced hepatocarcinogenesis: possible benefit in female transgenic mice.
BACKGROUND
C-myc activation is a potent oncogenic event in hepatocarcinogenesis. The aim of this study was to test the preventive effect of interferon-alpha (IFN-alpha) on the development of dysplasia and subsequent hepatocellular carcinoma (HCC) in transgenic (Tg) mice overexpressing c-myc in the liver.


METHODS
The WHV/c-myc Tg mice recapitulating woodchuck hepatitis virus-induced hepatocarcinogenesis were treated with IFN-alpha, starting early in life until sacrifice at pre-neoplastic or neoplastic stages. Transgene expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR), hepatocyte proliferation was assessed by bromodeoxyuridine incorporation and RT-PCR for proliferating cell nuclear antigen, and apoptosis was assessed by in situ nick-end-labeling of DNA.


RESULTS
C-myc expression and hepatocyte proliferation were significantly reduced in treated female mice, without modification of apoptosis, correlating with a lower severity of dysplasia in 9/12 treated animals at pre-neoplastic stages. At the neoplastic stage, 2/3 treated females neither exhibited carcinoma nor dysplasia, while all 6/6 untreated mice and 3/3 treated males developed carcinomas.


CONCLUSIONS
Inhibition of c-myc and hepatocyte proliferation by long-term administration of IFN-alpha was associated with a decrease, or a delay, of oncogenesis in the mouse Tg HCC model. Whether c-myc and hepatocyte proliferation down-regulation could be relevant parameters of IFN-alpha efficiency for hepatocarcinogenesis prevention in cirrhotic patients should be established.
Merle
P
P
INSERM Unit 271, Lyon, France.
Chevallier
M
M
Levy
R
R
Maisonnas
M
M
Terradillos
O
O
Ahmed SNS
Trépo
C
C
Buendia
M A
MA
Vitvitski-Trépo
L
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006509:Hepatitis B / Q000150:complications*; D017919:Hepatitis B Virus, Woodchuck; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use
D016898:Interferon-alpha; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins