A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

作者：Boege Yannick; Malehmir Mohsen; Healy Marc E; Bettermann Kira; Lorentzen Anna; Vucur Mihael; Ahuja Akshay K; Bohm Friederike; Mertens Joachim C; Shimizu Yutaka; Frick Lukas; Remouchamps Caroline; Mutreja Karun; Kaehne Thilo; Sundaravinayagam Devakumar; Wolf Monika J; Rehrauer Hubert; Koppe Christiane; Speicher Tobias; Padrissa Altes Susagna; Maire Renaud; Schattenberg Jo Rn M; Jeong Ju Seong; Liu Lei; Zwirner Stefan; Boger Regina; Hueser Norbert; Davis Roger J

来源：Cancer Cell, 2017, 32(3): 342-+.

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.

• 出版日期2017-9-11