Anti-tumor effect of pegylated interferon in the rat hepatocarcinogenesis model

Abstract

Abstract. 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 antitumor 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.

Effect of pegylated interferon therapy on intrahepatic recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma

“…Several reports have shown the inhibitory effects of IFN therapy on the development of HCC. In these reports, the inhibitory effect was considered to be the result of the remission of inflammation, necrosis, and fibrosis in addition to the direct action of IFN on tumor cells [35][36][37][38][39]. Recently, several studies were conducted to show the effect of IFN therapy after curative treatment of HCC, which reduced the risk for recurrence and improved the rate of survival.…”

Dynamic noninvasive markers predict hepatocellular carcinoma in chronic hepatitis C patients without sustained virological response after interferon-based therapy

“…Previous studies reported that AFP might enhance tumor cell growth and the proliferation of human hepatoma, and that IFN therapy, irrespective of viral eradication, reduced this risk. [ 30 – 33 ] Thus, non-SVR patients might have a reduced risk of HCC after IFN treatment due to their lower AFP levels. Therefore, the combined use of post-treatment AFP level and FIB4 index may provide a more precise prediction of the risk of HCC.…”

Notch1 activation contributes to tumor cell growth and proliferation in human hepatocellular carcinoma HepG2 and SMMC7721 cells

“…However, investigations from other teams come up with different results. A study shows that activation of Notch1 in the pre-neoplastic foci might be associated with the progression of HCC in the diethylnitrosamine-induced hepatocarcinogenesis model (31). Downregulation of Notch1 signaling by a Notch1 inhibitor curcumin, inhibits tumor growth in human HCC (32).…”