Abstract
BackgroundThe hepatitis C virus (HCV) is one of the major risk factors for the development of hepatocellular carcinoma (HCC). Nevertheless, transgenic mice which express the whole HCV polyprotein (HCV-Tg) do not develop HCC. Whereas chronic HCV infection causes inflammation in patients, in HCV-Tg mice, the host immune reaction against viral proteins is lacking. We aimed to test the role of HCV proteins in HCC development on the background of chronic inflammation in vivo.Methodology/Principal FindingsWe crossed HCV-Tg mice that do not develop HCC with the Mdr2-knockout (Mdr2-KO) mice which develop inflammation-associated HCC, to generate Mdr2-KO/HCV-Tg mice. We studied the effect of the HCV transgene on tumor incidence, hepatocyte mitosis and apoptosis, and investigated the potential contributing factors for the generated phenotype by gene expression and protein analyses. The Mdr2-KO/HCV-Tg females from the N2 generation of this breeding (having 75% of the FVB/N genome and 25% of the C57BL/6 genome) produced significantly larger tumors in comparison with Mdr2-KO mice. In parallel, the Mdr2-KO/HCV-Tg females had an enhanced inflammatory gene expression signature. However, in the N7 generation (having 99.2% of the FVB/N genome and 0.8% of the C57BL/6 genome) there was no difference in tumor development between Mdr2-KO/HCV-Tg and Mdr2-KO animals of both sexes. The HCV transgene was similarly expressed in the livers of Mdr2-KO/HCV-Tg females of both generations, as revealed by detection of the HCV transcript and the core protein.ConclusionThese findings suggest that the HCV transgene accelerated inflammation-associated hepatocarcinogenesis in a host genetic background-dependent manner.
Highlights
Hepatocellular carcinoma (HCC) is a significant health care burden worldwide, and chronic inflammation is a major risk factor for the development of hepatocellular carcinoma (HCC)
These findings suggest that the hepatitis C virus (HCV) transgene accelerated inflammation-associated hepatocarcinogenesis in a host genetic background-dependent manner
Levels of the HCV transgene expression were similar between Mdr2-KO/HCV transgenic (HCV-Tg) mice from the N2 and N7 generations (Fig. 1, A and B)
Summary
Hepatocellular carcinoma (HCC) is a significant health care burden worldwide, and chronic inflammation is a major risk factor for the development of HCC. The hepatitis C virus (HCV) is one of the major etiological HCC agents: it induces chronic liver inflammation and is responsible for the increased incidence of HCC in the developed world [1]. Non infectious metabolic conditions causing chronic hepatitis expose humans to an increased risk of developing HCC. The aim of this study is to investigate the interplay between the factors contributing to the development of HCC in a mouse model expressing HCV proteins. The hepatitis C virus (HCV) is one of the major risk factors for the development of hepatocellular carcinoma (HCC). Transgenic mice which express the whole HCV polyprotein (HCV-Tg) do not develop HCC. We aimed to test the role of HCV proteins in HCC development on the background of chronic inflammation in vivo
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