c‐Rel–dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis
0301 basic medicine
Cancer Research
Carcinoma, Hepatocellular
Original Articles: Liver Cancer
Carcinogenesis
Physiology
Hepatocellular carcinoma
DNA repair
Apoptosis
Cancer research
Gene
Mice
Cell growth
03 medical and health sciences
Biochemistry, Genetics and Molecular Biology
Role of Nrf2 Signaling in Oxidative Stress Response
Genetics
Animals
Humans
Chemotherapy
Molecular Biology
Biology
Cancer
Programmed cell death
Mice, Knockout
0303 health sciences
Molecular Physiology of Purinergic Signalling
Liver Neoplasms
NF-kappa B
Life Sciences
DNA
Proto-Oncogene Proteins c-rel
3. Good health
Doxorubicin
FOS: Biological sciences
Hepatocytes
DNA damage
Nucleotide Signalling
NF-?B Signaling in Inflammation and Cancer
Transcription factor
DNA Damage
DOI:
10.1002/hep.32781
Publication Date:
2022-09-12T01:09:50Z
AUTHORS (18)
ABSTRACT
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 (Rel
Alb
) 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.
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CITATIONS (8)
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