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

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.

doi:10.1016/j.ccell.2017.08.010

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

Details

Request a copy Under indefinite embargo.
UNIL restricted access
State: Public
Version: author
License: CC BY-NC-ND 4.0

Serval ID

serval:BIB_3B46F441361C

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

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

Number

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

OAI-PMH

oai:serval.unil.ch:BIB_3B46F441361C

DOI

10.1016/j.ccell.2017.08.010

Pubmed

28898696

Web of science

000410199600010

Open Access

Yes

Create date

28/09/2017 13:16