1. A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
- Author
-
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, and Weber A
- Subjects
- Animals, Apoptosis, Carcinoma, Hepatocellular pathology, Cell Proliferation, Cellular Senescence, Chronic Disease, Crosses, Genetic, 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 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, Carcinogenesis metabolism, Carcinogenesis pathology, Caspase 8 metabolism, DNA Damage, Liver Neoplasms enzymology, Liver Neoplasms pathology
- 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.)
- Published
- 2017
- Full Text
- View/download PDF