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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.

Cancer Cell 32, 342-359.e10 (2017)
Publishers Version DOI PMC
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Damage Response ; Apoptosis ; Hepatocellular Carcinoma ; Liver ; Replication Stress; Hepatocellular-carcinoma; Genotoxic Stress; Cell-proliferation; Chronic Hepatitis; Activation; Complex; Hepatocytes; Apoptosis; Mice; Gene
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