Anti-tumor effect of pegylated interferon in the rat hepatocarcinogenesis model.
Interferon (IFN) is a multifunctional cytokine which works as a suppressor of hepatocarcinogenesis. Pegylated interferon (PEG-IFN) is a modified form of IFN with different pharmacokinetics. We evaluated the anti-tumor effect of PEG-IFN using a rat hepatocarcinogenesis model. Male Fisher Rats were treated using the Solt and Faber model to induce liver cancer. IFN and PEG-IFN were administered from chemical initiation, and pre-neoplastic foci and neoplastic hepatocellular carcinoma (HCC) were examined at 4 and 40 weeks after chemical initiation, respectively. Apoptosis-related molecules such as p53 and Fas-L, proliferating cell nuclear antigen (PCNA), and oxidative stress-related molecules such as 8-hydroxydeoxyguanosine (8-OHdG) and thioredoxin (TRX) were assessed by immunohistochemical analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of Notch-1, a molecule related to the regenerative and oncogenic processes was also examined. The generation of foci and HCC were significantly suppressed in IFN and PEG-IFN groups compared with the control group. Whereas PCNA and Notch-1 were strongly expressed in the foci and HCC, Fas-L was mainly detected in the surrounding hepatocytes. 8-OHdG and TRX were also detected in the foci. Although PCNA and Notch-1 were down-regulated in IFN- and PEG-IFN-treated groups, Fas-L was up-regulated in those groups. The activation of Notch-1 signaling and the accumulation of oxidative stress in the pre-neoplastic foci might be associated with the progression of HCC in the DEN-induced hepatocarcinogenesis model. The inhibitory effect of the PEG-IFN and IFN on hepatocarcinogenesis was almost the same, and this might be induced by the Fas-related apoptosis in the surrounding tissues.
Miki
Akira
A
Division of Molecular Medicine and Medical Genetics, International Center of Medical Research and Treatment, Kobe University Graduate School of Medicine, Kusunoki-cho, Kobe 650-0017, Japan.
Yano
Yoshihiko
Y
Kato
Hirotaka
H
Seo
Yasushi
Y
Kuriyama
Masamitsu
M
Azuma
Takeshi
T
Hayashi
Yoshitake
Y
D015073:2-Acetylaminofluorene; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004052:Diethylnitrosamine; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry / Q000627:therapeutic use; D011230:Precancerous Conditions / Q000139:chemically induced; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D004052:Diethylnitrosamine; D011092:Polyethylene Glycols; D015073:2-Acetylaminofluorene; C100416:peginterferon alfa-2a