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Hösel M, Quasdorff M, Ringelhan M, et al. Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication. Cell Mol Gastroenterol Hepatol. 2017;4(3):339-363doi: 10.1016/j.jcmgh.2017.07.003.
Hösel, M., Quasdorff, M., Ringelhan, M., Kashkar, H., Debey-Pascher, S., Sprinzl, M. F., Bockmann, J. H., Arzberger, S., Webb, D., von Olshausen, G., Weber, A., Schultze, J. L., Büning, H., Heikenwalder, M., & Protzer, U. (2017). Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication. Cellular and molecular gastroenterology and hepatology, 4(3), 339-363. https://doi.org/10.1016/j.jcmgh.2017.07.003
Hösel, Marianna, et al. "Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication." Cellular and molecular gastroenterology and hepatology vol. 4,3 (2017): 339-363. doi: https://doi.org/10.1016/j.jcmgh.2017.07.003
Hösel M, Quasdorff M, Ringelhan M, Kashkar H, Debey-Pascher S, Sprinzl MF, Bockmann JH, Arzberger S, Webb D, von Olshausen G, Weber A, Schultze JL, Büning H, Heikenwalder M, Protzer U. Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication. Cell Mol Gastroenterol Hepatol. 2017 Jul 19;4(3):339-363. doi: 10.1016/j.jcmgh.2017.07.003. eCollection 2017 Nov. PMID: 28884137; PMCID: PMC5581872.
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Cell Mol Gastroenterol Hepatol. 2017 Jul 19;4(3):339-363. doi: 10.1016/j.jcmgh.2017.07.003. eCollection 2017 Nov.

Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication.

Cellular and molecular gastroenterology and hepatology

Marianna Hösel, Maria Quasdorff, Marc Ringelhan, Hamid Kashkar, Svenja Debey-Pascher, Martin F Sprinzl, Jan-Hendrik Bockmann, Silke Arzberger, Dennis Webb, Gesa von Olshausen, Achim Weber, Joachim L Schultze, Hildegard Büning, Mathias Heikenwalder, Ulrike Protzer

Affiliations

  1. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  2. Department of Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany.
  3. Institute of Virology, Technische Universität München / Helmholtz Zentrum München, Munich, Germany.
  4. Department of Internal Medicine II, University Hospital of the Technical University of Munich, Munich, Germany.
  5. Institute of Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany.
  6. Institute for Life and Medical Sciences, Genomics and Immunoregulation, University of Bonn, Bonn, Germany.
  7. 1 Medical Department, University Hospital Mainz, Mainz, Germany.
  8. German Centre for Infection Research, Partner sites Bonn-Cologne, Hannover-Braunschweig, Hamburg, and Munich, Germany.
  9. Department of Internal Medicine I, University Hospital of the Technical University of Munich, Munich, Germany.
  10. Institute of Surgical Pathology, University Hospital Zürich, Zürich, Switzerland.
  11. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
  12. Department Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.

PMID: 28884137 PMCID: PMC5581872 DOI: 10.1016/j.jcmgh.2017.07.003

Abstract

BACKGROUND & AIMS: The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma, but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection.

METHODS: We performed gene expression profiling of primary human hepatocytes infected with HBV and proved the results in HBV-replicating cell lines and human liver tissue using real-time polymerase chain reaction and Western blotting. Activation of signal transducer and activator of transcription (STAT3) was examined in HBV-replicating human hepatocytes, HBV-replicating mice, and liver tissue from HBV-infected individuals using Western blotting, STAT3-luciferase reporter assay, and immunohistochemistry. The consequences of STAT3 activation on HBV infection and cell survival were studied by chemical inhibition of STAT3 phosphorylation and small interfering RNA-mediated knockdown of STAT3.

RESULTS: Gene expression profiling of HBV-infected primary human hepatocytes detected no interferon response, while genes encoding for acute phase and antiapoptotic proteins were up-regulated. This gene regulation was confirmed in liver tissue samples of patients with chronic HBV infection and in HBV-related hepatocellular carcinoma. Pathway analysis revealed activation of STAT3 to be the major regulator. Interleukin-6-dependent and -independent activation of STAT3 was detected in HBV-replicating hepatocytes in cell culture and in vivo. Prevention of STAT3 activation by inhibition of Janus tyrosine kinases as well as small interfering RNA-mediated knockdown of STAT3-induced apoptosis and reduced HBV replication and gene expression.

CONCLUSIONS: HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells. This very likely supports HBV-related carcinogenesis.

Keywords: APR, acute phase response; Apoptosis; CRP, C-reactive protein; DMSO, dimethyl sulfoxide; FCS, fetal calf serum; HBV pg RNA, hepatitis B pregenomic RNA; HBV, Hepatitis B virus; HBVtg, hepatitis B transgenic; HBeAg, hepatitis B early antigen; HCC, hepatocellular carcinoma; HNF, hepatocyte nuclear factor; Hepatitis B Virus Infection; Hepatocellular Carcinoma; IFN, interferon; IL-6, interleukin 6; IRF3, interferon regulatory factor 3; NAC, N-acetyl-L-cysteine; PCR, polymerase chain reaction; PHH, primary human hepatocyte; ROS, reactive oxygen species; RT, reverse transcription; STAT3 Signaling; STAT3, signal transducer and activator of transcription 3; cDNA, complementary DNA; cRNA, complementary RNA; cccDNA, covalently closed circular DNA; mRNA, messenger RNA; p.i., postinfection; pSTAT3, phosphorylated signal transducer and activator of transcription 3; pgRNA, pregenomic RNA; siRNA, small interfering RNA

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