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
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (46)
CITATIONS (8)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....