半胱天冬酶-8在引发和感知增殖相关DNA损伤中的双重作用，这是肝癌发展的关键决定因素。
A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
作者信息
Boege Yannick, Malehmir Mohsen, Healy Marc E, Bettermann Kira, Lorentzen Anna, Vucur Mihael, Ahuja Akshay K, Böhm Friederike, Mertens Joachim C, Shimizu Yutaka, Frick Lukas, Remouchamps Caroline, Mutreja Karun, Kähne Thilo, Sundaravinayagam Devakumar, Wolf Monika J, Rehrauer Hubert, Koppe Christiane, Speicher Tobias, Padrissa-Altés Susagna, Maire Renaud, Schattenberg Jörn M, Jeong Ju-Seong, Liu Lei, Zwirner Stefan, Boger Regina, Hüser Norbert, Davis Roger J, Müllhaupt Beat, Moch Holger, Schulze-Bergkamen Henning, Clavien Pierre-Alain, Werner Sabine, Borsig Lubor, Luther Sanjiv A, Jost Philipp J, Weinlich Ricardo, Unger Kristian, Behrens Axel, Hillert Laura, Dillon Christopher, Di Virgilio Michela, Wallach David, Dejardin Emmanuel, Zender Lars, Naumann Michael, Walczak Henning, Green Douglas R, Lopes Massimo, Lavrik Inna, Luedde Tom, Heikenwalder Mathias, Weber Achim
机构信息
Department of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland.
Department of Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany.
出版信息
Cancer Cell. 2017 Sep 11;32(3):342-359.e10. doi: 10.1016/j.ccell.2017.08.010.
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.
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）的一个标志。在此，我们通过增殖和复制相关的DNA损伤，从机制上将半胱天冬酶-8依赖性凋亡与HCC发展联系起来。在CLD中，在任何肿瘤性变化发生之前，即可检测到增殖相关的复制应激、DNA损伤和基因不稳定。肝细胞凋亡的累积水平决定并预测随后的肝癌发生。增殖相关的DNA损伤由一个包含半胱天冬酶-8、FADD、c-FLIP和RIPK1激酶依赖性功能的复合物感知。该平台需要半胱天冬酶-8的非凋亡功能，但不需要半胱天冬酶-3或半胱天冬酶-8的切割。它可能代表了肝细胞中的一种DNA损伤传感机制，可通过JNK及随后组蛋白变体H2AX的磷酸化发挥作用。
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