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

Details

Serval ID
serval:BIB_3B46F441361C
Type
Article: article from journal or magazin.
Collection
Publications
Title
A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
Journal
Cancer Cell
Author(s)
Boege Y., Malehmir M., Healy M.E., Bettermann K., Lorentzen A., Vucur M., Ahuja A.K., Böhm F., Mertens J.C., Shimizu Y., Frick L., Remouchamps C., Mutreja K., Kähne T., Sundaravinayagam D., Wolf M.J., Rehrauer H., Koppe C., Speicher T., Padrissa-Altés S., Maire R., Schattenberg J.M., Jeong J.S., Liu L., Zwirner S., Boger R., Hüser N., Davis R.J., Müllhaupt B., Moch H., Schulze-Bergkamen H., Clavien P.A., Werner S., Borsig L., Luther S.A., Jost P.J., Weinlich R., Unger K., Behrens A., Hillert L., Dillon C., Di Virgilio M., Wallach D., Dejardin E., Zender L., Naumann M., Walczak H., Green D.R., Lopes M., Lavrik I., Luedde T., Heikenwalder M., Weber A.
ISSN
1878-3686 (Electronic)
ISSN-L
1535-6108
Publication state
Published
Issued date
2017
Peer-reviewed
Oui
Volume
32
Number
3
Pages
342-359.e10
Language
english
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
Animals, Apoptosis, Carcinogenesis/metabolism, Carcinogenesis/pathology, Carcinoma, Hepatocellular/pathology, Caspase 8/metabolism, Cell Aging, Cell Proliferation, Chronic Disease, Crosses, Genetic, DNA Damage, DNA Repair, Fas-Associated Death Domain Protein/metabolism, Female, Genomic Instability, Hepatectomy, Hepatocytes/pathology, Histones/metabolism, Humans, JNK Mitogen-Activated Protein Kinases/metabolism, Liver/metabolism, Liver/pathology, Liver Neoplasms/enzymology, Liver Neoplasms/pathology, Liver Regeneration, Male, Mice, Myeloid Cell Leukemia Sequence 1 Protein/metabolism, Phosphorylation, Receptor-Interacting Protein Serine-Threonine Kinases/metabolism, Receptors, Tumor Necrosis Factor, Type I/metabolism, Risk Factors, DNA damage response, apoptosis, hepatocellular carcinoma, liver, replication stress
Pubmed
Web of science
Open Access
Yes
Create date
28/09/2017 13:16
Last modification date
20/08/2019 13:31
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