A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
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DOI：
10.1016/j.ccell.2017.08.010
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发表时间：
2017-09-11
期刊：
影响因子：
50.3
通讯作者：
Weber A
中科院分区：
文献类型：
--
作者：
Boege Y;Malehmir M;Healy ME;Bettermann K;Lorentzen A;Vucur M;Ahuja AK;Böhm F;Mertens JC;Shimizu Y;Frick L;Remouchamps C;Mutreja K;Kähne T;Sundaravinayagam D;Wolf MJ;Rehrauer H;Koppe C;Speicher T;Padrissa-Altés S;Maire R;Schattenberg JM;Jeong JS;Liu L;Zwirner S;Boger R;Hüser N;Davis RJ;Müllhaupt B;Moch H;Schulze-Bergkamen H;Clavien PA;Werner S;Borsig L;Luther SA;Jost PJ;Weinlich R;Unger K;Behrens A;Hillert L;Dillon C;Di Virgilio M;Wallach D;Dejardin E;Zender L;Naumann M;Walczak H;Green DR;Lopes M;Lavrik I;Luedde T;Heikenwalder M;Weber A
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.
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影响因子：
29.4
作者：
Luedde T;Kaplowitz N;Schwabe RF
通讯作者：
Schwabe RF
影响因子：
9
作者：
Brown MF;Leibowitz BJ;Chen D;He K;Zou F;Sobol RW;Beer-Stolz D;Zhang L;Yu J
通讯作者：
Yu J
DOI：
10.15252/embj.201695699
发表时间：
2017-05-02
期刊：
The EMBO journal
影响因子：
--
作者：
Lafont E;Kantari-Mimoun C;Draber P;De Miguel D;Hartwig T;Reichert M;Kupka S;Shimizu Y;Taraborrelli L;Spit M;Sprick MR;Walczak H
通讯作者：
Walczak H
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影响因子：
9
作者：
通讯作者：
--
美国肝细胞癌的流行病学：我们在哪里？我们去哪里？
影响因子：
13.5
作者：
El-Serag, Hashem B.;Kanwal, Fasiha
通讯作者：
Kanwal, Fasiha