IFN-alpha prevents the growth of pre-neoplastic lesions and inhibits the development of hepatocellular carcinoma in the rat.
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 pre-neoplastic 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, in which hepatocellular carcinoma (HCC) arises through pre-neoplastic 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 pre-neoplastic 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 pre-neoplastic foci, using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). As a result of IFN-alpha treatment, the numbers and average volume of pre-neoplastic foci were reduced. The proliferating cell nuclear antigen index and the expression of G(1) cyclins were also reduced in the pre-neoplastic 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 weeks 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 with shorter treatment. In conclusion, it was shown that IFN-alpha directly prevented and delayed hepatocarcinogenesis through the suppression of pre-neoplastic cell proliferation and that it may partially depend on p21 induction through a p53-independent pathway.
Nakaji
Miyuki
M
Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-ku Kobe 650-0017, Japan.
Yano
Yoshihiko
Y
Ninomiya
Toshiaki
T
Seo
Yasushi
Y
Hamano
Kenichi
K
Yoon
Seitetsu
S
Kasuga
Masato
M
Teramoto
Tadahisa
T
Hayashi
Yoshitake
Y
Yokozaki
Hiroshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001835:Body Weight; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control*; D056741:Cyclin D; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D011230:Precancerous Conditions / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; C493958:Cdkn1a protein, rat; D056741:Cyclin D; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016898:Interferon-alpha; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53