A dual role of Caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development


  • Y. Boege
  • M. Malehmir
  • M.E. Healy
  • K. Bettermann
  • A. Lorentzen
  • M. Vucur
  • A.K. Ahuja
  • F. Böhm
  • J.C. Mertens
  • Y. Shimizu
  • L. Frick
  • C. Remouchamps
  • K. Mutreja
  • T. Kähne
  • D. Sundaravinayagam
  • M.J. Wolf
  • H. Rehrauer
  • C. Koppe
  • T. Speicher
  • S. Padrissa-Altés
  • R. Maire
  • J.M. Schattenberg
  • J.S. Jeong
  • Lei Liu
  • S. Zwirner
  • R. Boger
  • N. Hüser
  • R.J. Davis
  • B. Müllhaupt
  • H. Moch
  • H. Schulze-Bergkamen
  • P.A. Clavien
  • S. Werner
  • L. Borsig
  • S.A. Luther
  • P.J. Jost
  • R. Weinlich
  • K. Unger
  • A. Behrens
  • L. Hillert
  • C. Dillon
  • M. Di Virgilio
  • D. Wallach
  • E. Dejardin
  • L. Zender
  • M. Naumann
  • H. Walczak
  • D.R. Green
  • M. Lopes
  • I. Lavrik
  • T. Luedde
  • M. Heikenwalder
  • A. Weber


  • Cancer Cell


  • Canc Cell 32 (3): 342-359


  • 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.