Carcinogenesis Advance Access published online on November 21, 2003
Carcinogenesis, doi:10.1093/carcin/bgh028
© 2003 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Division of Diabetes, Digestive and Kidney Diseases, and Division of Surgical Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
* Corresponding author. E-mail: ninomiya{at}med.kobe-u.ac.jp.
Received 8 August 2003
; revised 19 October 2003
; accepted 11 November 2003
Interferon (IFN) -alpha treatment is a common therapy for chronic viral hepatitis and contributes to preventing hepatocarcinogenesis. However, it is not clear whether IFN-alpha directly inhibits the clonal expansion of preneoplastic hepatocytes. To clarify the mechanism by which IFN-alpha prevents hepatocarcinogenesis, we examined the effect of IFN-alpha in a chemically induced hepatocarcinogenesis model initiated by diethylnitrosamine (DEN) and promoted by 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH), in which hepatocellular carcinoma (HCC) arises through preneoplastic foci without inflammation or fibrosis. The protocols of IFN-alpha administration were started simultaneously with chemical initiation and lasted for either 4 or 40 weeks. The preneoplastic foci and neoplastic HCC were evaluated at 4 or 40 weeks after chemical initiation, respectively. The effects of IFN-alpha were assessed by the expression of tumor-related genes and cell cycle-related genes in the preneoplastic foci, using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). As a result of IFN-alpha treatment, the numbers and average volume of preneoplastic foci were reduced. The PCNA index and the expression of G1 cyclins were also reduced in the preneoplastic foci in the IFN-treated group. The expression of p21 which is an inhibitor of cyclin-kinase complexes was higher in the foci of the IFN-treated group, while p53 expression was not altered in this group, compared with the control group. IFN-alpha also suppressed the tumor development at 40 week after initiation. And in the long-term IFN-alpha-treated group, both the tumor numbers and average tumor size were markedly more reduced than those in the short-term treated group. Therefore, it was demonstrated that longer treatment with IFN-alpha was more effective, compared to shorter treatment. In conclusion, it was shown that IFN-alpha directly prevented and delayed hepatocarcinogenesis through the suppression of preneoplastic cell proliferation and that it may partially depend on p21 induction through a p53 independent pathway.
interferon-alpha, hepatocarcinogenesis, cell cycle, p21
IFN-alpha prevents the growth of preneoplastic lesions and inhibits the development of hepatocellular carcinoma in the rat
2 Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
3 Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan
4 Division of Molecular Medicine & Medical Genetics International Center for Medical Research (ICMR) Kobe University Graduate School of Medicine, Kobe, Japan
5 Division of Surgical Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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