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Sunami, Y.* ; Ringelhan, M. ; Kokai, E.* ; Lu, M.* ; O'Connor, T. ; Lorentzen, A.R. ; Weber, A.* ; Rodewald, A.K.* ; Müllhaupt, B.* ; Terracciano, L.* ; Gul, S.* ; Wissel, S.* ; Leithäuser, F. ; Krappmann, D.* ; Riedl, P.* ; Hartmann, D.* ; Schirmbeck, R.* ; Strnad, P.* ; Hüser, N.* ; Kleeff, J.* ; Friess, H.* ; Schmid, R.M.* ; Geisler, F.* ; Wirth, T.* ; Heikenwälder, M.

Canonical NF-κB signaling in hepatocytes acts as a tumor-suppressor in HBV surface antigen-driven HCC by controlling the UPR.

Hepatology 63, 1592-1607 (2016)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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. 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 (ER) stress already at 20 weeks of age in NF-κB-deficient hepatocytes of HBsAg-expressing mice. The unfolded protein response (UPR) regulator BiP/GRP78 was downregulated, ATF6 and eIF2α were activated with subsequent overexpression of CHOP. Notably, immune cell infiltrates and liver transaminases were unchanged. However, due to 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. CONCLUSION: 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 ER stress response. This article is protected by copyright. All rights reserved.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Bip ; Er Stress ; Hbsag ; Cancer ; Hepatitis B Virus; Endoplasmic-reticulum Stress; Fibrosing Cholestatic Hepatitis; Transgenic Mice; Nonalcoholic Steatohepatitis; Cancer Development; Liver-disease; Er Stress; Activation; Transcription; Pathogenesis
ISSN (print) / ISBN 0270-9139
e-ISSN 1527-3350
Zeitschrift Hepatology
Quellenangaben Band: 63, Heft: 5, Seiten: 1592-1607 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Hoboken, NJ
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Research Unit Signaling and Translation (SAT)