%0 Journal Article
%@ 1535-6108
%A Boege, Y
%A Malehmir, M
%A Healy, ME
%A Bettermann, K
%A Lorentzen, A
%A Vucur, M
%A Ahuja, AK
%A Böhm, F
%A Mertens, JC
%A Shimizu, Y
%A Frick, L
%A Remouchamps, C
%A Mutreja, K
%A Kähne, T
%A Sundaravinayagam, D
%A Wolf, MJ
%A Rehrauer, H
%A Koppe, C
%A Speicher, T
%A Padrissa-Altés, S
%A Maire, R
%A Schattenberg, JRM
%A Jeong, J-S
%A Liu, L
%A Zwirner, S
%A Boger, R
%A Hüser, N
%A Davis, RJ
%A Müllhaupt, B
%A Moch, H
%A Schulze-Bergkamen, H
%A Clavien, P-A
%A Werner, S
%A Borsig, L
%A Luther, SA
%A Jost, PJ
%A Weinlich, R
%A Unger, K
%A Behrens, A
%A Hillert, L
%A Dillon, C
%A Di Virgilio, M
%A Wallach, D
%A Dejardin, E
%A Zender, L
%A Naumann, M
%A Walczak, H
%A Green, DR
%A Lopes, M
%A Lavrik, I
%A Luedde, T
%A Heikenwalder, M
%A Weber, A
%D 2017
%F discovery:10049372
%I CELL PRESS
%J Cancer Cell
%K liver, hepatocellular carcinoma, DNA damage response, replication stress, apoptosis
%N 3
%P 342-359
%T A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development
%U https://discovery.ucl.ac.uk/id/eprint/10049372/
%V 32
%X 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.
%Z © 2017 The Authors. Published by Elsevier Inc. This is an Open Access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).