Animals; Apoptosis; Carcinogenesis/metabolism/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/pathology; Liver Neoplasms/enzymology/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; DNA damage response; hepatocellular carcinoma; liver; replication stress
Abstract :
[en] 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.
Dejardin, Emmanuel ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo of Molecular Immunol. and Signal Transduction
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