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  • A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.

Cancer cell (2017-09-13)
Yannick Boege, Mohsen Malehmir, Marc E Healy, Kira Bettermann, Anna Lorentzen, Mihael Vucur, Akshay K Ahuja, Friederike Böhm, Joachim C Mertens, Yutaka Shimizu, Lukas Frick, Caroline Remouchamps, Karun Mutreja, Thilo Kähne, Devakumar Sundaravinayagam, Monika J Wolf, Hubert Rehrauer, Christiane Koppe, Tobias Speicher, Susagna Padrissa-Altés, Renaud Maire, Jörn M Schattenberg, Ju-Seong Jeong, Lei Liu, Stefan Zwirner, Regina Boger, Norbert Hüser, Roger J Davis, Beat Müllhaupt, Holger Moch, Henning Schulze-Bergkamen, Pierre-Alain Clavien, Sabine Werner, Lubor Borsig, Sanjiv A Luther, Philipp J Jost, Ricardo Weinlich, Kristian Unger, Axel Behrens, Laura Hillert, Christopher Dillon, Michela Di Virgilio, David Wallach, Emmanuel Dejardin, Lars Zender, Michael Naumann, Henning Walczak, Douglas R Green, Massimo Lopes, Inna Lavrik, Tom Luedde, Mathias Heikenwalder, Achim Weber
PMID28898696
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.

MATERIALS
Product Number
Brand
Product Description
F3665
Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O111:B4, FITC conjugate