TY  - JOUR
Y1  - 2017/09/11/
UR  - https://doi.org/10.1016/j.ccell.2017.08.010
ID  - discovery10049372
N2  - 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.
SP  - 342
VL  - 32
JF  - Cancer Cell
A1  - Boege, Y
A1  - Malehmir, M
A1  - Healy, ME
A1  - Bettermann, K
A1  - Lorentzen, A
A1  - Vucur, M
A1  - Ahuja, AK
A1  - Böhm, F
A1  - Mertens, JC
A1  - Shimizu, Y
A1  - Frick, L
A1  - Remouchamps, C
A1  - Mutreja, K
A1  - Kähne, T
A1  - Sundaravinayagam, D
A1  - Wolf, MJ
A1  - Rehrauer, H
A1  - Koppe, C
A1  - Speicher, T
A1  - Padrissa-Altés, S
A1  - Maire, R
A1  - Schattenberg, JRM
A1  - Jeong, J-S
A1  - Liu, L
A1  - Zwirner, S
A1  - Boger, R
A1  - Hüser, N
A1  - Davis, RJ
A1  - Müllhaupt, B
A1  - Moch, H
A1  - Schulze-Bergkamen, H
A1  - Clavien, P-A
A1  - Werner, S
A1  - Borsig, L
A1  - Luther, SA
A1  - Jost, PJ
A1  - Weinlich, R
A1  - Unger, K
A1  - Behrens, A
A1  - Hillert, L
A1  - Dillon, C
A1  - Di Virgilio, M
A1  - Wallach, D
A1  - Dejardin, E
A1  - Zender, L
A1  - Naumann, M
A1  - Walczak, H
A1  - Green, DR
A1  - Lopes, M
A1  - Lavrik, I
A1  - Luedde, T
A1  - Heikenwalder, M
A1  - Weber, A
PB  - CELL PRESS
AV  - public
SN  - 1535-6108
TI  - A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development
EP  - 359
IS  - 3
N1  - © 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/).
KW  - liver
KW  -  hepatocellular carcinoma
KW  -  DNA damage response
KW  -  replication stress
KW  -  apoptosis
ER  -