Hepatitis C-associated liver carcinogenesis: Role of PML nuclear bodies

Abstract

Successful escape from immune response characterises chronic hepatitis C virus (HCV) infection, which results in persistence of infection in about 80% of the patients. The deleterious consequences are cirrhosis and hepatocellular carcinoma. HCV accounts the most frequent cause for hepatocellular carcinoma (HCC) and liver transplantation (LT) in the western world. The underlying molecular mechanisms how HCV promotes tumor development are largely unknown. There is some in vitro and in vivo evidence that HCV interferes with the tumor suppressor PML and may thereby importantly contribute to the HCV-associated pathogenesis with respect to the development of HCC. The tumor suppressor protein “promyelocytic leukemia” (PML) has been implicated in the regulation of important cellular processes like differentiation and apoptosis. In cancer biology, PML and its associated nuclear bodies (NBs) have initially attracted intense interest due to its role in the pathogenesis of acute promyelocytic leukemia (APL). More recently, loss of PML has been implicated in human cancers of various histologic origins. Moreover, number and intensity of PML-NBs increase in response to interferons (IFNs) and there is evidence that PML-NBs may represent preferential targets in viral infections. Thus, PML could not only play a role in the mechanisms of the antiviral action of IFNs but may also be involved in a direct oncogenic effect of the HCV on hepatocytes. This review aims to summarise current knowledge about HCV-related liver carcinogenesis and to discuss a potential role of the nuclear body protein PML for this this hard-to-treat cancer.

Keywords: Hepatitis C virus, Promyelocytic leukemia, Nuclear bodies, Hepatocellular carcinoma, Apoptosis

Core tip: Escape from immune response and non-responsiveness to interferon-therapy are frequently observed in hepatitis C virus (HCV) infection. HCV infection leads to severe liver disease like cirrhosis and hepatocellular carcinoma and is the major cause for hepatocellular carcinoma and liver transplantation in the western world. Interestingly, HCV interferes with tumor suppressor promyelocytic leukemia (PML) function in apoptosis. PML localises to multi-protein complexes termed nuclear bodies (NBs). The number and the size of PML NBs are increased upon interferon-treatment and PML NBs represent preferential targets in viral infection. Accordingly, PML plays an important role in the antiviral action of interferons.