1 Department of Laboratory Sciences, Faculty of Health Sciences, and 2 Department of Gastroenterology and Hepatology, Faculty of Medicine, Yamaguchi University, School of Medicine, Ube, Yamaguchi, 7558505, Japan
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Abstract |
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Keywords: cell cycle, hepatocellular carcinoma, MEK/ERK pathway, oxidative stress
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Introduction |
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A number of large-scale, retrospective, cohort studies conducted in Japan have demonstrated that interferon therapy reduces the incidence of HCC, not only in sustained virological responders but also in transient biochemical responders, without eliminating HCV (Table 1).16 On the other hand, the incidence of HCC has been shown to increase 5 years or more after interferon therapy in transient biochemical responders, suggesting that, in this population, interferons effects are time sensitive.7 In this respect, we demonstrated that re-treatment with interferon at certain intervals reduced the incidence of HCC in patients with chronic hepatitis C, even if eradication of HCV was not achieved by re-treatment.8 It seems plausible that eradicating HCV would result in a reduced incidence of HCC. We cannot, however, explain how a transient normalization of serum alanine aminotransferase (ALT) levels, induced by a maximum 6 months of interferon treatment, reduces the incidence of HCC during the progression of chronic hepatitis to cirrhosis or HCC, which requires dozens of years. We discuss herein how interferon treatment might reduce the incidence of HCC even in transient biochemical responders.
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Hypercarcinogenic condition in HCV-associated chronic hepatitis or liver cirrhosis |
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A recent study has revealed that protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A and Wee1 are significantly elevated in HCV-associated HCC compared with surrounding cirrhotic tissues.16 More importantly, these kinases are already activated in cirrhosis before the development of HCC, compared with normal liver tissues, suggesting that this activation is an early event in hepatocarcinogenesis and that HCV-associated cirrhosis is a pre-cancerous condition. Thus, in a chronic hepatitis state, the cell cycle progresses and hepatocytes divide rapidly. As a result, irregular regeneration is bound to happen, accelerating genomic instability. Of course, the MEK/ERK pathway is not the only pathway potentially leading to the development of HCC. For, instance, there is considerable interest in the wnt/ß-catenin pathway, specifically in the context of HCV-associated HCC.17 The complexity of all the biochemical pathways implicated in HCC development is well described in a broad review on the genetics of HCC.18
Another scenario for hepatocarcinogenesis in HCV infection is the involvement of oxidative stress, which can produce genetic mutations as well as gross chromosomal alterations. HCV core protein has been shown to produce reactive oxygen species (ROS) derived from mitochondria in inducible cell culture systems.19 A positive feedback effect of ROS on mitochondrial ROS generation further sensitizes cells to other oxidative insults, which may finally cause both mitochondrial and chromosomal DNA damage. In a transgenic mouse model for HCV-associated hepatocarcinogenesis, it is also demonstrated that HCV core protein causes a state of oxidative stress in the absence of inflammation.20
Although these results suggest the direct induction of oxidative stress by HCV proteins, the consequences of impaired mitochondrial function and abnormal ROS generation would be exacerbated by the immune-mediated inflammatory process present in patients with chronic hepatitis C, and the additional oxidant load it would present to the HCV-infected liver. Continuous ROS generation is likely to cause 8-hydroxy-2'-deoxyguanosine (8-OHdG) to accumulate in DNA. Kato et al.21 reported that lowering levels of 8-OHdG by phlebotomy potentially decreased the risk of hepatocarcinogenesis in patients with chronic hepatitis C. According to them, hepatic 8-OHdG levels decreased significantly in the short-term (initial iron reduction phase) and were almost completely normalized by the end of therapy (6 years later) by keeping a state of mild iron deficiency, defined by either <10 µg/L serum ferritin and/or 11 g/dL blood haemoglobin concentration. Thus, oxidative stress appears to be responsible, in part, for the development of HCV-associated HCC.
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Clinical evidence suggesting the anti-hepatocarcinogenic effect of interferon in patients with HCV-associated chronic liver disease |
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A recent randomized study has shown that interferon-ß prevents the recurrence of HCC after complete resection or ablation of the primary tumour in patients with HCV-associated cirrhosis.24 This inhibitory effect on HCC recurrence by interferon was not associated with biochemical and virological improvement. Therefore, these results clearly suggest that interferon acts as an anti-hepatocarcinogenic agent in patients with HCV-associated chronic liver diseases.
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Molecular mechanism by which interferon prevents hepatocarcinogenesis in patients with chronic hepatitis C |
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Interferon- has been shown to reduce intrarenal oxidative stress in rats with carbon tetrachloride-induced nephrotoxicity.29 Another study revealed that interferon-
dose-dependently increased the protein levels of copper-, zinc- and manganese-dependent superoxide dismutase, as well as the enzyme activities of glutathione peroxidase, and decreased the lipid peroxidation product levels in oxidative-stressed rat hepatocytes.30 As HCV RNA levels are usually decreased or undetectable, even though uncommonly unchanged, during interferon therapy in transient biochemical responders, such antioxidative actions of interferon may be amplified in a condition where oxidative stress is attenuated due to decreased HCV load. In fact, 2 months interferon therapy has been shown to decrease the serum lipid peroxidation products (thiobarbituric acid reactive substances) of hepatitis C patients, whose serum ALT levels fall to the normal range.31
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Conclusions |
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There is no strong clinical evidence linking the antioxidative action of interferon to the inhibition of HCC development in patients with chronic hepatitis C. Thus, further studies are required to determine how the antioxidative activity of interferon is involved in reducing the HCC incidence in HCV infection.
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Acknowledgements |
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Footnotes |
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References |
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