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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

Summary 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. Proliferat...

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Hauptverfasser: Böge, Yannick Thimotheus (VerfasserIn) , Boger, Regina (VerfasserIn) , Schulze-Bergkamen, Henning (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: September 11, 2017
In: Cancer cell
Year: 2017, Jahrgang: 32, Heft: 3, Pages: 342-359.e1-e10
ISSN:1878-3686
DOI:10.1016/j.ccell.2017.08.010
Online-Zugang:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1016/j.ccell.2017.08.010
Verlag, kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S1535610817303549
Volltext
Verfasserangaben: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, and Achim Weber
Beschreibung
Zusammenfassung:Summary 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.
Beschreibung:Gesehen am 20.09.2018
Beschreibung:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2017.08.010

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