A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development
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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000191884Publication status
publishedExternal links
Journal / series
Cancer CellVolume
Pages / Article No.
Publisher
Cell PressSubject
liver; Hepatocellular carcinoma; DNA damage response; replication stress; apoptosisOrganisational unit
03520 - Werner, Sabine / Werner, Sabine
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
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