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SHR Neuro Cancer Cardio Lipid Metab Microb
Boege, Y; Malehmir, M; Healy, ME; Bettermann, K; Lorentzen, A; Vucur, M; Ahuja, AK; Böhm, F; Mertens, JC; Shimizu, Y; Frick, L; Remouchamps, C; Mutreja, K; Kähne, T; Sundaravinayagam, D; Wolf, MJ; Rehrauer, H; Koppe, C; Speicher, T; Padrissa-Altés, S; Maire, R; Schattenberg, JM; Jeong, JS; Liu, L; Zwirner, S; Boger, R; Hüser, N; Davis, RJ; Müllhaupt, B; Moch, H; Schulze-Bergkamen, H; Clavien, PA; Werner, S; Borsig, L; Luther, SA; Jost, PJ; Weinlich, R; Unger, K; Behrens, A; Hillert, L; Dillon, C; Di Virgilio, M; Wallach, D; Dejardin, E; Zender, L; Naumann, M; Walczak, H; Green, DR; Lopes, M; Lavrik, I; Luedde, T; Heikenwalder, M; Weber, A.
A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
Cancer Cell. 2017; 32(3):342-359
Doi: 10.1016/j.ccell.2017.08.010
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- Co-authors Med Uni Graz
- Jost Philipp
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- 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. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apoptosis -
- Carcinogenesis - metabolism
- Carcinogenesis - 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
- Liver - pathology
- Liver Neoplasms - enzymology
- Liver Neoplasms - 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 -