title: Canonical NF-κB signaling in hepatocytes acts as a tumor-suppressor in hepatitis B virus surface antigen-driven hepatocellular carcinoma by controlling the unfolded protein response.
abstract: Chronic hepatitis B virus (HBV) infection remains the most common risk factor for hepatocellular carcinoma (HCC). Efficient suppression of HBV viremia and necroinflammation as a result of nucleos(t)ide analogue treatment is able to reduce HCC incidence; nevertheless, hepatocarcinogenesis can occur in the absence of active hepatitis, correlating with high HBV surface antigen (HBsAg) levels. Nuclear factor κB (NF-κB) is a central player in chronic inflammation and HCC development. However, in the absence of severe chronic inflammation, the role of NF-κB signaling in HCC development remains elusive. As a model of hepatocarcinogenesis driven by accumulation of HBV envelope polypeptides, HBsAg transgenic mice, which show no HBV-specific immune response, were crossed to animals with hepatocyte-specific inhibition of canonical NF-κB signaling. We detected prolonged, severe endoplasmic reticulum stress already at 20 weeks of age in NF-κB-deficient hepatocytes of HBsAg-expressing mice. The unfolded protein response regulator binding immunoglobulin protein/78-kDa glucose-regulated protein was down-regulated, activating transcription factor 6, and eIF2α were activated with subsequent overexpression of CCAAT/enhancer binding protein homologous protein. Notably, immune cell infiltrates and liver transaminases were unchanged. However, as a result of this increased cellular stress, insufficient hepatocyte proliferation due to G1 /S-phase cell cycle arrest with overexpression of p27 and emergence of ductular reactions was detected. This culminated in increased DNA damage already at 20 weeks of age and finally led to 100% HCC incidence due to NF-κB inhibition.
  
  
  CONCLUSIONS
  The role of canonical NF-κB signaling in HCC development depends on the mode of liver damage; in the case of HBsAg-driven hepatocarcinogenesis, NF-κB in hepatocytes acts as a critical tumor suppressor by augmenting the endoplasmic reticulum stress response.
authors.affiliation: Department of General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.|Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sunami
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.|Institute of Virology, Technical University Munich/Helmholtz Zentrum Munich, Munich, Germany.|German Center for Infection research (DZIF), Munich partner site, Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ringelhan
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Enikö
authors.initials: E
authors.lastname: Kokai
authors.affiliation: Department of General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Miao
authors.initials: M
authors.lastname: Lu
authors.affiliation: Institute of Virology, Technical University Munich/Helmholtz Zentrum Munich, Munich, Germany.
authors.forename: Tracy
authors.initials: T
authors.lastname: O'Connor
authors.affiliation: Institute of Virology, Technical University Munich/Helmholtz Zentrum Munich, Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Lorentzen
authors.affiliation: Institute of Surgical Pathology, Zürich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Surgical Pathology, Zürich, Switzerland.
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Rodewald
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gul
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wissel
authors.affiliation: Institute of Pathology, University Medical Center Ulm, Ulm, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.affiliation: Research Unit Cellular Signal Integration, Helmholtz Zentrum Munich, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Riedl
authors.affiliation: Department of General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartmann
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.affiliation: Department of Medicine III and IZKF, University Hospital Aachen, Aachen, Germany.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.affiliation: Department of General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hüser
authors.affiliation: Department of General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Department of General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Geisler
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.affiliation: Institute of Virology, Technical University Munich/Helmholtz Zentrum Munich, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control*; D059447:Cell Cycle Checkpoints; D006514:Hepatitis B Surface Antigens / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000150:complications; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control*; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D056811:Unfolded Protein Response
chemical_list: C497250:Ddit3 protein, mouse; D006514:Hepatitis B Surface Antigens; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D051742:Transcription Factor CHOP