Abstract
BackgroundHepatocellular carcinoma (HCC) is a common complication of chronic viral hepatitis. In support of this notion, we have reported that hepatitis B surface antigen (HBsAg)-specific CD8+ T lymphocytes critically contribute to inducing chronic liver cell injury that exerts high carcinogenic potential in a hepatitis B virus (HBV) transgenic mouse model. The dynamics of the molecular signatures responsible for hepatocellular carcinogenesis are not fully understood. The current study was designed to determine the serial changes in gene expression profiles in a model of chronic immune-mediated hepatitis.MethodsThree-month-old HBV transgenic mice were immunologically reconstituted with bone marrow cells and splenocytes from syngeneic nontransgenic donors. Liver tissues were obtained every three months until 18 months at which time all mice developed multiple liver tumors. Nitrative DNA lesions and hepatocyte turnover were assessed immunohistochemically. Gene expression profiles were generated by extracting total RNA from the tissues and analyzing by microarray.ResultsThe nitrative DNA lesions and the regenerative proliferation of hepatocytes were increased during the progression of chronic liver disease. In a gene expression profile analysis of liver samples, the chemokine- and T cell receptor (TCR)-mediated pathways were enhanced during chronic hepatitis, and the EGF- and VEGF-mediated pathways were induced in HCC. Among these molecules, the protein levels of STAT3 were greatly enhanced in all hepatocyte nuclei and further elevated in the cytoplasm in HCC tissue samples at 18 months, and the levels of phosphorylated TP53 (p-p53-Ser 6 and -Ser 15) were increased in liver tissues.ConclusionsHBV-specific immune responses caused unique molecular signatures in the liver tissues of chronic hepatitis and triggered subsequent carcinogenic gene expression profiles in a mouse model. The results suggest a plausible molecular basis responsible for HBV-induced immune pathogenesis of HCC.
Highlights
IntroductionThe development of hepatocellular carcinoma (HCC) is a complex multifactorial process in which many years of chronic hepatitis plays a major role.[1, 2] In patients with chronic hepatitis B and C, the virus-specific CD4+ and CD8+ T lymphocytes have been reported to play a role in the immunopathogenesis of liver disease.[3,4,5,6] In transgenic mouse models of hepatitis B virus (HBV), transfer of CD4+ and CD8+ T cell clones specific for the viral antigens induced acute liver cell injury.[7,8,9] In an effort to evaluate the carcinogenic potential of chronic inflammation, we have established a model of prolonged immune-mediated hepatitis using HBV transgenic mice that express the viral envelope proteins in their hepatocytes.[10]the lymphocyte subset transfer revealed that the pathogenetic events caused by CD8+ cytotoxic T lymphocytes (CTLs) are primarily responsible for the development of chronic liver disease that enhances tumor incidence.[11]CD8+ CTL-induced continuous inflammation is sufficient to trigger the process of hepatocarcinogenesis in the absence of preexisting viral transactivation or genetic changes in chronic HBV infection.[10, 12, 13] During the process of cancer development, molecular events may accumulate in intracellular and extracellular microenvironments to establish the pathological signatures of tumor tissues distinct from non-cancer conditions
Hepatocellular carcinoma (HCC) is a common complication of chronic viral hepatitis. In support of this notion, we have reported that hepatitis B surface antigen (HBsAg)-specific CD8+ T lymphocytes critically contribute to inducing chronic liver cell injury that exerts high carcinogenic potential in a hepatitis B virus (HBV) transgenic mouse model
In a gene expression profile analysis of liver samples, the chemokine- and T cell receptor (TCR)-mediated pathways were enhanced during chronic hepatitis, and the EGF- and VEGF-mediated pathways were induced in hepatocellular carcinoma (HCC)
Summary
The development of hepatocellular carcinoma (HCC) is a complex multifactorial process in which many years of chronic hepatitis plays a major role.[1, 2] In patients with chronic hepatitis B and C, the virus-specific CD4+ and CD8+ T lymphocytes have been reported to play a role in the immunopathogenesis of liver disease.[3,4,5,6] In transgenic mouse models of hepatitis B virus (HBV), transfer of CD4+ and CD8+ T cell clones specific for the viral antigens induced acute liver cell injury.[7,8,9] In an effort to evaluate the carcinogenic potential of chronic inflammation, we have established a model of prolonged immune-mediated hepatitis using HBV transgenic mice that express the viral envelope proteins in their hepatocytes.[10]the lymphocyte subset transfer revealed that the pathogenetic events caused by CD8+ cytotoxic T lymphocytes (CTLs) are primarily responsible for the development of chronic liver disease that enhances tumor incidence.[11]CD8+ CTL-induced continuous inflammation is sufficient to trigger the process of hepatocarcinogenesis in the absence of preexisting viral transactivation or genetic changes in chronic HBV infection.[10, 12, 13] During the process of cancer development, molecular events may accumulate in intracellular and extracellular microenvironments to establish the pathological signatures of tumor tissues distinct from non-cancer conditions. The development of hepatocellular carcinoma (HCC) is a complex multifactorial process in which many years of chronic hepatitis plays a major role.[1, 2] In patients with chronic hepatitis B and C, the virus-specific CD4+ and CD8+ T lymphocytes have been reported to play a role in the immunopathogenesis of liver disease.[3,4,5,6] In transgenic mouse models of hepatitis B virus (HBV), transfer of CD4+ and CD8+ T cell clones specific for the viral antigens induced acute liver cell injury.[7,8,9] In an effort to evaluate the carcinogenic potential of chronic inflammation, we have established a model of prolonged immune-mediated hepatitis using HBV transgenic mice that express the viral envelope proteins in their hepatocytes.[10]. Hepatocellular carcinoma (HCC) is a common complication of chronic viral hepatitis In support of this notion, we have reported that hepatitis B surface antigen (HBsAg)-specific CD8+ T lymphocytes critically contribute to inducing chronic liver cell injury that exerts high carcinogenic potential in a hepatitis B virus (HBV) transgenic mouse model. The current study was designed to determine the serial changes in gene expression profiles in a model of chronic immune-mediated hepatitis.
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