UMMS Affiliation

Program in Molecular Medicine; Davis Lab; UMass Metabolic Network

Publication Date

2017-09-11

Document Type

Article

Disciplines

Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology

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.

Rights and Permissions

© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

DOI of Published Version

10.1016/j.ccell.2017.08.010

Source

Cancer Cell. 2017 Sep 11;32(3):342-359.e10. doi: 10.1016/j.ccell.2017.08.010. Link to article on publisher's site

Journal/Book/Conference Title

Cancer cell

Comments

Full list of authors omitted for brevity. For full list see article.

Related Resources

Link to Article in PubMed

PubMed ID

28898696

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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