期刊
CANCER CELL
卷 32, 期 3, 页码 342-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2017.08.010
关键词
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资金
- Krebsliga Schweiz (Oncosuisse)
- Promedica Stiftung, Stiftung zur Krebsbekampfung, Zurich
- Swiss National Research Foundation (SNF) [310030_146940/1]
- Helmholtz Association
- Stiftung Experimentelle Biomedizin'' (Hofschneider Foundation)
- European Research Council (ERC Consolidator Grant, HepatoMetaboPath)
- Graduierten Kolleg (GRK) [482]
- Sonderforschungsbereiche (SFB) [36, 179, 209]
- European Union [667273]
- Mildred-Scheel Endowed Professorship
- German Cancer Aid (Deutsche Krebshilfe [110043]
- German Research Foundation [SFB-TRR57/P06]
- SNF [310030_132884]
- DFG [FOR2314, SFB685, DFG-LA 2386]
- Gottfried Wilhelm Leibniz Program
- NIH [DK107220]
- Hartmann Muller Stiftung and PhD program of the Cancer Network Zurich
- The Francis Crick Institute [10039] Funding Source: researchfish
- Swiss National Science Foundation (SNF) [310030_146940] Funding Source: Swiss National Science Foundation (SNF)
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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