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A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
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.
Animals, Apoptosis, Carcinogenesis/metabolism, Carcinogenesis/pathology, Carcinoma, Hepatocellular/pathology, Caspase 8/metabolism, Cell Aging, Cell Proliferation, 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, DNA damage response, apoptosis, hepatocellular carcinoma, liver, replication stress
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