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

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

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Pages (from-to)339-363
Number of pages25
JournalCMGH
Volume4
Issue number3
DOIs
StatePublished - Nov 2017

Keywords

  • Apoptosis
  • Hepatitis B Virus Infection
  • Hepatocellular Carcinoma
  • STAT3 Signaling

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