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A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
Cancer Cell ( IF 50.3 ) Pub Date : 2017-09-11 , DOI: 10.1016/j.ccell.2017.08.010
Yannick Boege , Mohsen Malehmir , Marc E. Healy , Kira Bettermann , Anna Lorentzen , Mihael Vucur , Akshay K. Ahuja , Friederike Böhm , Joachim C. Mertens , Yutaka Shimizu , Lukas Frick , Caroline Remouchamps , Karun Mutreja , Thilo Kähne , Devakumar Sundaravinayagam , Monika J. Wolf , Hubert Rehrauer , Christiane Koppe , Tobias Speicher , Susagna Padrissa-Altés , Renaud Maire , Jörn M. Schattenberg , Ju-Seong Jeong , Lei Liu , Stefan Zwirner , Regina Boger , Norbert Hüser , Roger J. Davis , Beat Müllhaupt , Holger Moch , Henning Schulze-Bergkamen , Pierre-Alain Clavien , Sabine Werner , Lubor Borsig , Sanjiv A. Luther , Philipp J. Jost , Ricardo Weinlich , Kristian Unger , Axel Behrens , Laura Hillert , Christopher Dillon , Michela Di Virgilio , David Wallach , Emmanuel Dejardin , Lars Zender , Michael Naumann , Henning Walczak , Douglas R. Green , Massimo Lopes , Inna Lavrik , Tom Luedde , Mathias Heikenwalder , Achim Weber

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.

中文翻译:

Caspase-8在触发和感知与增殖相关的DNA损伤中的双重作用,这是决定肝癌发展的关键因素。

伴随的肝细胞凋亡和再生是易患肝细胞癌(HCC)的慢性肝病(CLD)的标志。在这里,我们通过增殖和复制相关的DNA损伤将caspase-8依赖的细胞凋亡机制性地联系到肝癌的发展。在任何肿瘤改变发生之前,可在CLD中检测到与增殖相关的复制压力,DNA损伤和遗传不稳定性。肝细胞凋亡的累积水平决定并预测随后的肝癌发生。与增殖相关的DNA损伤可通过一种复合物来感知,该复合物包含caspase-8,FADD,c-FLIP和RIPK1的激酶依赖性功能。该平台需要caspase-8的非凋亡功能,但不需要caspase-3或caspase-8裂解。
更新日期:2017-09-11
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