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c-Rel–dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis

Lookup NU author(s): Dr Jack LeslieORCiD, Dr Jill Hunter, Amy Collins, Amelia Rushton, Lauren Russell, Erik Ramon Gil, Maja Laszczewska, Misti McCainORCiD, Marco Youssef William Zaki, Amber Knox, Laura Sabater, Dr Daniel Geh, Professor Neil PerkinsORCiD, Professor Helen ReevesORCiD, Dr Dina Tiniakos, Professor Derek Mann, Professor Fiona OakleyORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. Background and Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c-Rel in HCC. Approach and Results: Histological and transcriptional studies confirmed expression of c-Rel in human patients with HCC, but low c-Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo, global (Rel−/−) and epithelial specific (RelAlb) c-Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild-type (WT) controls 30 weeks after N-diethylnitrosamine injury. However, tumor burden was comparable when c-Rel was deleted in hepatocytes once tumors were established, suggesting c-Rel signaling is important for preventing HCC initiation after genotoxic injury, rather than for HCC progression. In vitro, Rel−/− hepatocytes were more susceptible to genotoxic injury than WT controls. ATM-CHK2 DNA damage response pathway proteins were suppressed in Rel−/− hepatocytes following genotoxic injury, suggesting that c-Rel is required for effective DNA repair. To determine if c-Rel inhibition sensitizes cancer cells to chemotherapy, by preventing repair of chemotherapy-induced DNA damage, thus increasing tumor cell death, we administered single or combination doxorubicin and IT-603 (c-Rel inhibitor) therapy in an orthotopic HCC model. Indeed, combination therapy was more efficacious than doxorubicin alone. Conclusion: Hepatocyte c-Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c-Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.


Publication metadata

Author(s): Leslie J, Hunter JE, Collins A, Rushton A, Russell LG, Ramon-Gil E, Laszczewska M, McCain M, Zaki MYW, Knox A, Seow Y, Sabater L, Geh D, Perkins ND, Reeves HL, Tiniakos D, Mann DA, Oakley F

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2023

Volume: 78

Issue: 4

Pages: 1050-1063

Print publication date: 01/10/2023

Online publication date: 11/09/2022

Acceptance date: 08/09/2022

Date deposited: 21/12/2022

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/hep.32781

DOI: 10.1002/hep.32781

PubMed id: 36089330


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Funding

Funder referenceFunder name
C1443/A22095Cancer Research UK CRUK (open competition)
C18342/A23390Cancer Research UK CRUK (open competition)
L016354
MR/R023026/1Medical Research Council (MRC)
MR/K0019494/1

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