ArticleCancer cell2017
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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Article in Cancer cell, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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92citing papers in PubMed
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92 citing papers in PubMed, 156 citations in OpenAlex.
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- Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated Steatohepatitis Post-dietary Intervention.Journal of clinical and translational hepatology · 2024Article
32 more citing papers are in PubMed but not listed here.
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Authors and funding
53 authors at 20 institutions in 6 countries.
Yannick BoegeDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Mohsen MalehmirDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Marc E HealyDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Kira BettermannDepartment of Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
Anna LorentzenInstitute of Virology, Technische Universität München, Helmholtz Zentrum München, 85764 Munich, Germany.
Mihael VucurDepartment of Medicine III, Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, 52056 Aachen, Germany.
Akshay K AhujaInstitute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
Friederike BöhmDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Joachim C MertensGastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland.
Yutaka ShimizuCentre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Lukas FrickDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Caroline RemouchampsLaboratory of Molecular Immunology and Signal Transduction, GIGA-R, University of Liège, 4000 Liège, Belgium.
Karun MutrejaInstitute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
Thilo KähneInstitute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
Devakumar SundaravinayagamDNA Repair and Maintenance of Genome Stability, Max-Delbruck Center for Molecular Medicine (MDC) Berlin, 13125 Berlin, Germany.
Monika J WolfDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Hubert RehrauerFunctional Genomics Center Zurich, ETH and University Zurich, 8057 Zurich, Switzerland.
Christiane KoppeDepartment of Medicine III, Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, 52056 Aachen, Germany.
Tobias SpeicherDepartment of Biology, Institute of Molecular Health Sciences, ETH, Zurich, Switzerland.
Susagna Padrissa-AltésDepartment of Biology, Institute of Molecular Health Sciences, ETH, Zurich, Switzerland.
Renaud MaireDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Jörn M SchattenbergI. Department of Medicine, University Medical Center, Johannes Gutenberg-University, 55122 Mainz, Germany.
Ju-Seong JeongDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Lei LiuDepartment of Surgery, Technische Universität München, 80333 Munich, Germany.
Stefan ZwirnerDepartment 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.
Regina BogerNational Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
Norbert HüserDepartment of Surgery, Technische Universität München, 80333 Munich, Germany.
Roger J DavisHoward Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Beat MüllhauptGastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland.
Holger MochDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Henning Schulze-BergkamenNational Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
Pierre-Alain ClavienClinic of Visceral and Transplantation Surgery, University Hospital Zurich, 8091 Zurich, Switzerland.
Sabine WernerDepartment of Biology, Institute of Molecular Health Sciences, ETH, Zurich, Switzerland.
Lubor BorsigInstitute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
Sanjiv A LutherDepartment of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Philipp J JostIII. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Ricardo WeinlichDepartment of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Kristian UngerResearch Unit Radiation Cytogenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Axel BehrensAdult Stem Cell Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Laura HillertDepartment of Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
Christopher DillonDepartment of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Michela Di VirgilioDNA Repair and Maintenance of Genome Stability, Max-Delbruck Center for Molecular Medicine (MDC) Berlin, 13125 Berlin, Germany.
David WallachDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Emmanuel DejardinLaboratory of Molecular Immunology and Signal Transduction, GIGA-R, University of Liège, 4000 Liège, Belgium.
Lars ZenderDepartment 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.
Michael NaumannInstitute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
Henning WalczakCentre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Douglas R GreenDepartment of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Massimo LopesInstitute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
Inna LavrikDepartment of Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
Tom LueddeDepartment of Medicine III, Division of GI and Hepatobiliary Oncology, University Hospital RWTH Aachen, 52056 Aachen, Germany.
Mathias HeikenwalderDepartment 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.
Achim WeberDepartment of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: achim.weber@usz.ch.
University Hospital of Zurich · CHOtto-von-Guericke University Magdeburg · DEUniversity of Zurich · CHETH Zurich · CHRWTH Aachen University · DESt. Jude Children's Research Hospital · USTechnical University of Munich · DEHelmholtz Zentrum München · DEMax Delbrück Center · DENational Center for Tumor Diseases · DEUniversity of Liège · BEWeizmann Institute of Science · ILCRUK Lung Cancer Centre of Excellence · GBGerman Cancer Research Center · DEHoward Hughes Medical Institute · USKlinikum rechts der Isar · DEThe Francis Crick Institute · GBUniversity College London · GBUniversity Medical Center of the Johannes Gutenberg University Mainz · DEUniversity of Lausanne · CH
Funding
Survival Function of the Fadd-Caspase-8-Flip ComplexR01AI044828 · NIAID · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI GREEN, DOUGLAS R. · 1999 to 2016
$6.3MSurvival Function of the Fadd-Caspase-8-Flip Complex - MERIT ExtensionR37AI044828 · NIAID · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI Douglas R. Green · 2017 to 2026
$4.5MMetabolic Stress SignalingR01DK107220 · NIDDK · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI DAVIS, ROGER J. · 2016 to 2023
$3.6MNIAID NIH HHS R01 AI044828NIAID NIH HHS R37 AI044828NIDDK NIH HHS R01 DK107220
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.
Indexed as
DNA DamageAnimalsApoptosisCarcinogenesisCarcinoma, HepatocellularCaspase 8Cell ProliferationCellular SenescenceChronic DiseaseCrosses, GeneticDNA RepairFas-Associated Death Domain ProteinFemaleGenomic InstabilityHepatectomyHepatocytesCaspase 8Fadd protein, mouseFas-Associated Death Domain Proteingamma-H2AX protein, mouseHistonesJNK Mitogen-Activated Protein KinasesMcl1 protein, mouseMyeloid Cell Leukemia Sequence 1 ProteinReceptor-Interacting Protein Serine-Threonine KinasesReceptors, Tumor Necrosis Factor, Type IRipk1 protein, mouseapoptosisDNA damage responsehepatocellular carcinomaliverreplication stress
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