6533b862fe1ef96bd12c61fe
RESEARCH PRODUCT
A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development.
Lubor BorsigNorbert HüserKristian UngerLukas FrickAxel BehrensMichela Di VirgilioDavid WallachCaroline RemouchampsSusagna Padrissa-altésJörn M. SchattenbergJu-seong JeongMonika Julia WolfRj BogerJoachim C. MertensYannick BoegeMihael VucurHenning Schulze-bergkamenRicardo WeinlichYutaka ShimizuAnna LorentzenTobias SpeicherHubert RehrauerHenning WalczakSabine WernerLei LiuLars ZenderLars ZenderMassimo LopesPhilipp J. JostMarc E. HealyMohsen MalehmirChristiane KoppeMathias HeikenwalderMathias HeikenwalderMichael NaumannDevakumar SundaravinayagamThilo KähnePierre-alain ClavienKarun MutrejaHolger MochDouglas R. GreenTom LueddeRoger J. DavisFriederike BöhmEmmanuel DejardinChristopher P. DillonStefan ZwirnerStefan ZwirnerLaura K. HillertKira BettermannRenaud MaireAkshay K. AhujaInna N. LavrikSanjiv A. LutherBeat MüllhauptAchim Webersubject
0301 basic medicineGenome instabilityMaleliver; Hepatocellular carcinoma; DNA damage response; replication stress; apoptosisCancer ResearchDNA RepairCarcinogenesisFas-Associated Death Domain ProteinApoptosisurologic and male genital diseasesDNA damage responseDna Damage Response ; Apoptosis ; Hepatocellular Carcinoma ; Liver ; Replication StressHistonesMice0302 clinical medicineRisk FactorsFADDPhosphorylationCellular SenescenceCaspase 8biologyLiver Neoplasmshepatocellular carcinomaLiver regeneration3. Good healthHistoneOncologyReceptors Tumor Necrosis Factor Type I030220 oncology & carcinogenesisReceptor-Interacting Protein Serine-Threonine KinasesFemalebiological phenomena cell phenomena and immunityCell agingCarcinoma HepatocellularDNA damageDNA repairreplication stressCaspase 8liverArticleGenomic Instability03 medical and health sciencesAnimalsHepatectomyHumansCrosses GeneticCell ProliferationJNK Mitogen-Activated Protein KinasesCell BiologyLiver Regeneration030104 developmental biologyImmunologyChronic Diseasebiology.proteinCancer researchHepatocytesMyeloid Cell Leukemia Sequence 1 ProteinDNA Damagedescription
Summary 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-09-11 |