A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development
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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 Toggle all authors (53)
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.
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Publisher website (DOI) 10.1016/j.ccell.2017.08.010
Europe PubMed Central 28898696
Pubmed 28898696
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