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Cancer Cell. 2017 Sep 11;32(3):342-359.e10. doi: 10.1016/j.ccell.2017.08.010.

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

Author information

1
Department of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
2
Department of Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
3
Institute of Virology, Technische Universität München, Helmholtz Zentrum München, 85764 Munich, Germany.
4
Department of Medicine III, Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, 52056 Aachen, Germany.
5
Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
6
Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland.
7
Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
8
Laboratory of Molecular Immunology and Signal Transduction, GIGA-R, University of Liège, 4000 Liège, Belgium.
9
Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
10
DNA Repair and Maintenance of Genome Stability, Max-Delbruck Center for Molecular Medicine (MDC) Berlin, 13125 Berlin, Germany.
11
Functional Genomics Center Zurich, ETH and University Zurich, 8057 Zurich, Switzerland.
12
Department of Biology, Institute of Molecular Health Sciences, ETH, Zurich, Switzerland.
13
I. Department of Medicine, University Medical Center, Johannes Gutenberg-University, 55122 Mainz, Germany.
14
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
15
Department of Surgery, Technische Universität München, 80333 Munich, Germany.
16
Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
17
National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
18
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
19
Clinic of Visceral and Transplantation Surgery, University Hospital Zurich, 8091 Zurich, Switzerland.
20
Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
21
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
22
III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
23
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
24
Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
25
Adult Stem Cell Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
26
Department of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland; Institute of Virology, Technische Universität München, Helmholtz Zentrum München, 85764 Munich, Germany; Institute of Chronic Inflammation and Cancer, Deutsches Krebs-Forschungszentrum (DKFZ), 69120 Heidelberg, Germany. Electronic address: m.heikenwaelder@dkfz.de.
27
Department of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: achim.weber@usz.ch.

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.

KEYWORDS:

DNA damage response; apoptosis; hepatocellular carcinoma; liver; replication stress

PMID:
28898696
PMCID:
PMC5598544
DOI:
10.1016/j.ccell.2017.08.010
[Indexed for MEDLINE]
Free PMC Article

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