%L discovery10049372
%K liver, hepatocellular carcinoma, DNA damage response, replication stress, apoptosis
%J Cancer Cell
%I CELL PRESS
%O © 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/).
%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.
%N 3
%V 32
%A Y Boege
%A M Malehmir
%A ME Healy
%A K Bettermann
%A A Lorentzen
%A M Vucur
%A AK Ahuja
%A F Böhm
%A JC Mertens
%A Y Shimizu
%A L Frick
%A C Remouchamps
%A K Mutreja
%A T Kähne
%A D Sundaravinayagam
%A MJ Wolf
%A H Rehrauer
%A C Koppe
%A T Speicher
%A S Padrissa-Altés
%A R Maire
%A JRM Schattenberg
%A J-S Jeong
%A L Liu
%A S Zwirner
%A R Boger
%A N Hüser
%A RJ Davis
%A B Müllhaupt
%A H Moch
%A H Schulze-Bergkamen
%A P-A Clavien
%A S Werner
%A L Borsig
%A SA Luther
%A PJ Jost
%A R Weinlich
%A K Unger
%A A Behrens
%A L Hillert
%A C Dillon
%A M Di Virgilio
%A D Wallach
%A E Dejardin
%A L Zender
%A M Naumann
%A H Walczak
%A DR Green
%A M Lopes
%A I Lavrik
%A T Luedde
%A M Heikenwalder
%A A Weber
%T A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development
%D 2017
%P 342-359