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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.

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.
AuthorsYannick 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
JournalCancer cell (Cancer Cell) Vol. 32 Issue 3 Pg. 342-359.e10 (09 11 2017) ISSN: 1878-3686 [Electronic] United States
PMID28898696 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Histones
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Receptors, Tumor Necrosis Factor, Type I
  • gamma-H2AX protein, mouse
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 8
Topics
  • Animals
  • Apoptosis
  • Carcinogenesis (metabolism, pathology)
  • Carcinoma, Hepatocellular (pathology)
  • Caspase 8 (metabolism)
  • Cell Proliferation
  • Cellular Senescence
  • Chronic Disease
  • Crosses, Genetic
  • DNA Damage
  • DNA Repair
  • Fas-Associated Death Domain Protein (metabolism)
  • Female
  • Genomic Instability
  • Hepatectomy
  • Hepatocytes (pathology)
  • Histones (metabolism)
  • Humans
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Liver (metabolism, pathology)
  • Liver Neoplasms (enzymology, pathology)
  • Liver Regeneration
  • Male
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
  • Phosphorylation
  • Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
  • Receptors, Tumor Necrosis Factor, Type I (metabolism)
  • Risk Factors

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