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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
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.
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: 2022
Issue: ePub ahead of Print
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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