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. •Hepatocyte apoptosis decisively determines and predicts HCC development•A non-apoptotic caspase-8/RIPK1/FADD/c-FLIP complex senses DNA damage•Caspase-8 deficiency is associated with impaired phosphorylation of H2AX•Low caspase-8 expression in HCC is associated with less aggressive behavior Boege et al. identify persistent hepatocyte apoptosis as a determinant of hepatocellular carcinoma development. They show that caspase-8 not only executes hepatocyte apoptosis but also has a non-apoptotic role in proliferation-associated DNA damage response mediated by a caspase-8/RIPK1/FADD/c-FLIP complex.