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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

Item Type:Article
Title:A dual role of Caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development
Creators Name:Boege, Y. and Malehmir, M. and Healy, M.E. and Bettermann, K. and Lorentzen, A. and Vucur, M. and Ahuja, A.K. and Boehm, F. and Mertens, J.C. and Shimizu, Y. and Frick, L. and Remouchamps, C. and Mutreja, K. and Kaehne, T. and Sundaravinayagam, D. and Wolf, M.J. and Rehrauer, H. and Koppe, C. and Speicher, T. and Padrissa-Altes, S. and Maire, R. and Schattenberg, J.M. and Jeong, J.S. and Liu, Lei and Zwirner, S. and Boger, R. and Hueser, N. and Davis, R.J. and Muellhaupt, B. and Moch, H. and Schulze-Bergkamen, H. and Clavien, P.A. and Werner, S. and Borsig, L. and Luther, S.A. and Jost, P.J. and Weinlich, R. and Unger, K. and Behrens, A. and Hillert, L. and Dillon, C. and Di Virgilio, M. and Wallach, D. and Dejardin, E. and Zender, L. and Naumann, M. and Walczak, H. and Green, D.R. and Lopes, M. and Lavrik, I. and Luedde, T. and Heikenwalder, M. and Weber, A.
Abstract: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.
Keywords:Liver, Hepatocellular Carcinoma, DNA Damage Response, Replication Stress, Apoptosis, Animals, Mice
Source:Cancer Cell
ISSN:1535-6108
Volume:32
Number:3
Page Range:342-359.e10
Date:11 September 2017
Official Publication:https://doi.org/10.1016/j.ccell.2017.08.010
PubMed:View item in PubMed

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