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

• DOI: 10.1002/hep.32781
• Publication Date: 2022-09-12T01:09:50Z
• Authors: Jack Leslie; Jill E. Hunter; Amy Collins; Amelia Rushton; Lauren G. Russell; Erik Ramon‐Gil; Maja Laszczewska; Misti McCain; Marco Y. W. Zaki; Amber Knox; Yixin Seow; Laura Sabater; Daniel Geh; Neil D. Perkins; Helen L. Reeves; Dina Tiniakos; Derek A. Mann; Fiona Oakley
• Keywords: 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; 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

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