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

5 years ago

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

Kähne T, Schulze-Bergkamen H, Walczak H, Lopes M, Malehmir M, Wallach D, Jost PJ, Boege Y, Borsig L, Werner S, Boger R, Remouchamps C, Heikenwalder M, Luedde T, Schattenberg JM, Weinlich R, Speicher T, Lavrik I, Unger K, Clavien PA, Ahuja AK, Hillert L, Moch H, Koppe C, Naumann M, Bettermann K, Sundaravinayagam D, Vucur M, Di Virgilio M, Zwirner S, Jeong JS, Wolf MJ, Lorentzen A, Dejardin E, Luther SA, Davis RJ, Zender L, Dillon C, Behrens A, Böhm F, Shimizu Y, Mertens JC, Weber A, Maire R, Hüser N, Liu L, Green DR, Padrissa-Altés S, Müllhaupt B, Healy ME, Mutreja K, Frick L, Rehrauer H

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.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28898696

DOI: PubMed:28898696