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

被引：160

作者：

Boege, Yannick ^{[1
,2
]}

Malehmir, Mohsen ^{[1
,2
]}

Healy, Marc E. ^{[1
,2
]}

Bettermann, Kira ^{[3
]}

Lorentzen, Anna ^{[4
]}

Vucur, Mihael ^{[5
]}

Ahuja, Akshay K. ^{[6
]}

Bohm, Friederike ^{[1
,2
]}

Mertens, Joachim C. ^{[7
]}

Shimizu, Yutaka ^{[8
]}

Frick, Lukas ^{[1
,2
]}

Remouchamps, Caroline ^{[9
]}

Mutreja, Karun ^{[6
]}

Kaehne, Thilo ^{[10
]}

Sundaravinayagam, Devakumar ^{[11
]}

Wolf, Monika J. ^{[1
,2
]}

Rehrauer, Hubert ^{[12
,13
]}

Koppe, Christiane ^{[5
]}

Speicher, Tobias ^{[14
]}

Padrissa-Altes, Susagna ^{[14
]}

Maire, Renaud ^{[1
,2
]}

Schattenberg, Jo Rn M. ^{[15
]}

Jeong, Ju-Seong ^{[16
]}

Liu, Lei ^{[17
]}

Zwirner, Stefan ^{[18
,19
,20
]}

Boger, Regina ^{[21
]}

Hueser, Norbert ^{[17
]}

Davis, Roger J. ^{[22
]}

Mullhaupt, Beat ^{[7
]}

Moch, Holger ^{[1
,2
]}

Schulze-Bergkamen, Henning ^{[21
]}

Clavien, Pierre-Alain ^{[23
]}

Werner, Sabine ^{[14
]}

Borsig, Lubor ^{[24
]}

Luther, Sanjiv A. ^{[25
]}

Jost, Philipp J. ^{[26
]}

Weinlich, Ricardo ^{[27
]}

Unger, Kristian ^{[28
]}

Behrens, Axel ^{[29
]}

Hillert, Laura ^{[3
]}

Dillon, Christopher ^{[27
]}

Di Virgilio, Michela ^{[11
]}

Wallach, David ^{[16
]}

Dejardin, Emmanuel ^{[9
]}

Zender, Lars ^{[18
,19
,20
]}

Naumann, Michael ^{[10
]}

Walczak, Henning ^{[8
]}

Green, Douglas R. ^{[27
]}

Lopes, Massimo ^{[6
]}

Lavrik, Inna ^{[3
]}

机构：

[1] Univ Zurich, Dept Pathol & Mol Pathol, CH-8091 Zurich, Switzerland

[2] Univ Hosp Zurich, CH-8091 Zurich, Switzerland

[3] Otto von Guericke Univ, Inst Expt Internal Med, Dept Translat Inflammat Res, D-39120 Magdeburg, Germany

[4] Tech Univ Munich, Inst Virol, Helmholtz Zentrum Munchen, D-85764 Munich, Germany

[5] Univ Hosp RWTH Aachen, Div GI & Hepatobiliary Oncol, Dept Med 3, D-52056 Aachen, Germany

[6] Univ Zurich, Inst Mol Canc Res, CH-8057 Zurich, Switzerland

[7] Univ Hosp Zurich, Gastroenterol & Hepatol, CH-8091 Zurich, Switzerland

[8] UCL, UCL Canc Inst, Dept Canc Biol, Ctr Cell Death Canc & Inflammat, London WC1E 6DD, England

[9] Univ Liege, Lab Mol Immunol & Signal Transduct, GIGA R, B-4000 Liege, Belgium

[10] Otto von Guericke Univ, Inst Expt Internal Med, D-39120 Magdeburg, Germany

[11] Max Delbruck Ctr Mol Med MDC Berlin, DNA Repair & Maintenance Genome Stabil, D-13125 Berlin, Germany

[12] ETH, Funct Genom Ctr Zurich, CH-8057 Zurich, Switzerland

[13] Univ Zurich, CH-8057 Zurich, Switzerland

[14] ETH, Inst Mol Hlth Sci, Dept Biol, Zurich, Switzerland

[15] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Med 1, D-55122 Mainz, Germany

[16] Weizmann Inst Sci, Dept Biomol Sci, IL-7610001 Rehovot, Israel

[17] Tech Univ Munich, Dept Surg, D-80333 Munich, Germany

[18] Univ Hosp Tubingen, Dept Internal Med 8, D-72076 Tubingen, Germany

[19] Eberhard Karls Univ Tubingen, Inst Physiol, Dept Physiol 1, D-72076 Tubingen, Germany

[20] German Canc Res Ctr, Translat Gastrointestinal Oncol Grp, German Consortium Translat Canc Res DKTK, D-69120 Heidelberg, Germany

[21] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany

[22] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA

[23] Univ Hosp Zurich, Clin Visceral & Transplantat Surg, CH-8091 Zurich, Switzerland

[24] Univ Zurich, Inst Physiol, CH-8057 Zurich, Switzerland

[25] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland

[26] Tech Univ Munich, Med Klin 3, Klinikum Rechts Isar, D-81675 Munich, Germany

[27] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA

[28] Helmholtz Zentrum Munchen, Res Unit Radiat Cytogenet, D-85764 Neuherberg, Germany

[29] Francis Crick Inst, Adult Stem Cell Lab, London NW1 1AT, England

[30] Deutsch Krebs Forschungszentrum DKFZ, Inst Chron Inflammat & Canc, D-69120 Heidelberg, Germany

来源：

CANCER CELL | 2017年 / 32卷 / 03期

基金：

瑞士国家科学基金会; 新加坡国家研究基金会; 欧洲研究理事会;

关键词：

HEPATOCELLULAR-CARCINOMA; GENOTOXIC STRESS; CELL-PROLIFERATION; CHRONIC HEPATITIS; ACTIVATION; COMPLEX; HEPATOCYTES; APOPTOSIS; MICE; GENE;

D O I：

10.1016/j.ccell.2017.08.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：342 / +

页数：28

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