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Boege, Y.* ; Malehmir, M.* ; Healy, M.E.* ; Bettermann, K.* ; Lorentzen, A.R. ; Vucur, M.* ; Ahuja, A.K.* ; Böhm, F.* ; Mertens, J.C.* ; Shimizu, Y.* ; Frick, L.* ; Remouchamps, C.* ; Mutreja, K.* ; Kähne, T.* ; Sundaravinayagam, D.* ; Wolf, M.J.* ; Rehrauer, H.* ; Koppe, C.* ; Speicher, T.* ; Padrissa-Altés, S.* ; Maire, R.* ; Schattenberg, J.M.* ; Jeong, J.S.* ; Liu, L.* ; Zwirner, S.* ; Boger, R.H.* ; Hüser, N.* ; Davis, R.J.* ; Müllhaupt, B.* ; Moch, H.* ; Schulze-Bergkamen, H.* ; Clavien, P.A.* ; Werner, S.* ; Borsig, L.* ; Luther, S.A.* ; Jost, P.J.* ; Weinlich, R.* ; Unger, K. ; Behrens, A.* ; Hillert, L.* ; Dillon, C.* ; Di Virgilio, M.* ; Wallach, D.* ; Dejardin, E.* ; Zender, L.* ; Naumann, M.* ; Walczak, H.* ; Green, D.R.* ; Lopes, M.* ; Lavrik, I.N.* ; Luedde, T.* ; Heikenwälder, M. ; Weber, A.*

A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development.

Cancer Cell 32, 342-359.e10 (2017)
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Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Damage Response ; Apoptosis ; Hepatocellular Carcinoma ; Liver ; Replication Stress; Hepatocellular-carcinoma; Genotoxic Stress; Cell-proliferation; Chronic Hepatitis; Activation; Complex; Hepatocytes; Apoptosis; Mice; Gene
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 1535-6108
e-ISSN 1878-3686
Journal Cancer Cell
Quellenangaben Volume: 32, Issue: 3, Pages: 342-359.e10 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
Radiation Sciences
PSP Element(s) G-551600-001
G-501000-001
PubMed ID 28898696
DOI 10.1016/j.ccell.2017.08.010
WOS ID WOS:000410199600010
Scopus ID 85030448207
Erfassungsdatum 2017-09-21
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