Abstract
Hepatitis B virus (HBV) is a major etiological factor of hepatocellular carcinoma (HCC). However, the precise pathogenetic mechanisms linking HBV infection and HCC remain uncertain. It has been reported that decreased antioxidant enzyme activities are associated with severe liver injury and hepatocarcinogenesis in mouse models. It is unclear if HBV can interfere with the activities of antioxidant enzymes. We established a HBV transgenic mouse line, which spontaneously developed HCC at 2 years of age. We studied the activities of the antioxidant enzymes in the liver of the HBV transgenic mice. Our results showed that the antioxidant enzymes glutathione peroxidase and superoxide dismutase 2 were down-regulated in HBV transgenic mice and correlated with JNK activation. HBV enhanced the Fas-mediated activation of caspase 6, caspase 8 and JNK without enhancing the activation of caspase 3 and hepatocellular apoptosis. As a proper redox balance is important for maintaining cellular homeostasis, these effects of HBV on the host antioxidant system and Fas-signaling may play an important role in HBV-induced hepatocarcinogenesis.
Highlights
Intracellular reactive oxygen species (ROS) levels are tightly controlled by four primary antioxidant enzymes superoxide dismutase (SOD) 1 and 2 (CuZnSOD and MnSOD), glutathione peroxidase (GPx) and catalase
Since activation of Jun amino-terminal kinases (JNK) has been observed in Hepatocellula carcinoma (HCC) mouse models and HCC patients [9,10,12], five hepatitis B virus (HBV) transgenic mice and seven nontransgenic control mice at two years of age were carefully identified by genotyping and chosen to study the activation of JNK in the liver
We determined whether or not JNK is activated in the liver of 2-year-old HBV transgenic mice, which developed HCC, and non-transgenic control mice by analyzing the levels of JNK1, JNK2 and their activated forms (i.e., p-JNK1 and p-JNK2) by Western blot (Fig. 1A)
Summary
Intracellular reactive oxygen species (ROS) levels are tightly controlled by four primary antioxidant enzymes superoxide dismutase (SOD) 1 and 2 (CuZnSOD and MnSOD), glutathione peroxidase (GPx) and catalase. Oxidative stress can result from increased production of ROS and/or diminished levels of antioxidants including the activities of antioxidant enzymes [3]. There are several published reports to show that decreased antioxidant enzyme activities are associated with severe liver injury and hepatocarcinogenesis in mouse models. When challenged with oxidant paraquat, C-Jun amino-terminal kinases (JNK) are more activated in GPx deficient mice than in wild type mice [7]. The correlation between aberrant activation of JNK and hepatocarcinogenesis is observed in liver-specific deletion of p38a and IKKb mouse models [9,10]. In a liver-specific deletion of IKKb mouse model, diethylnitrosamine (DEN)-induced ROS production may contribute to sustained JNK activation due to oxidation and inhibition of JNK-inactivating phosphatases [11]. The mechanism for JNK1 activation is unknown [12]
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