A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
Loading...
Embargo End Date
ICR Authors
Authors
Boege, Y
Malehmir, M
Healy, ME
Bettermann, K
Lorentzen, A
Vucur, M
Ahuja, AK
Böhm, F
Mertens, JC
Shimizu, Y
Frick, L
Remouchamps, C
Mutreja, K
Kähne, T
Sundaravinayagam, D
Wolf, MJ
Rehrauer, H
Koppe, C
Speicher, T
Padrissa-Altés, S
Maire, R
Schattenberg, JM
Jeong, J-S
Liu, L
Zwirner, S
Boger, R
Hüser, N
Davis, RJ
Müllhaupt, B
Moch, H
Schulze-Bergkamen, H
Clavien, P-A
Werner, S
Borsig, L
Luther, SA
Jost, PJ
Weinlich, R
Unger, K
Behrens, A
Hillert, L
Dillon, C
Di Virgilio, M
Wallach, D
Dejardin, E
Zender, L
Naumann, M
Walczak, H
Green, DR
Lopes, M
Lavrik, I
Luedde, T
Heikenwalder, M
Weber, A
Malehmir, M
Healy, ME
Bettermann, K
Lorentzen, A
Vucur, M
Ahuja, AK
Böhm, F
Mertens, JC
Shimizu, Y
Frick, L
Remouchamps, C
Mutreja, K
Kähne, T
Sundaravinayagam, D
Wolf, MJ
Rehrauer, H
Koppe, C
Speicher, T
Padrissa-Altés, S
Maire, R
Schattenberg, JM
Jeong, J-S
Liu, L
Zwirner, S
Boger, R
Hüser, N
Davis, RJ
Müllhaupt, B
Moch, H
Schulze-Bergkamen, H
Clavien, P-A
Werner, S
Borsig, L
Luther, SA
Jost, PJ
Weinlich, R
Unger, K
Behrens, A
Hillert, L
Dillon, C
Di Virgilio, M
Wallach, D
Dejardin, E
Zender, L
Naumann, M
Walczak, H
Green, DR
Lopes, M
Lavrik, I
Luedde, T
Heikenwalder, M
Weber, A
Document Type
Journal Article
Date
2017-09-11
Date Accepted
2017-08-16
Abstract
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.
Citation
Cancer Cell, 2017, 32 (3), pp. 342 - 359.e10
Source Title
Cancer Cell
Publisher
CELL PRESS
ISSN
1535-6108
eISSN
1878-3686
Collections
Research Team
Convergence SC Management