Fiche publication
Date publication
mai 2026
Journal
Cancers
Auteurs
Membres identifiés du Cancéropôle Est :
Dr EGLY Jean-Marc
Tous les auteurs :
Chang TK, Li SL, Brunac AC, Huang JJ, Yeh YH, Brousset P, Egly JM, Li TK
Lien Pubmed
Résumé
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), increase colorectal cancer (CRC) risk. Mouse IBD and CRC models with a combination of pharmacological, knockout and knock-in approaches was employed to analyze the involvement of TOP2s and NOS2 in CRC tumorigenesis. Key pathologies, such as inflammatory and neoplastic scores, were examined by immunohistochemical assays. In colon tissues from acute, chronic colitis and CRC mouse models and from CD patients, the biomarkers γH2AX and 53BP1 of DNA breaks (mainly representing DSBs) accumulated, alongside increases in topoisomerase II (TOP2) and nitric oxide synthase 2 (NOS2). Genetic ablation of NOS2 () or TOP2β () as well as pharmacological inhibition with ICRF-193 (a TOP2 inhibitor) or PTIO (a NO scavenger) reduced DSB formation and disease severity. Consistently, , or ICRF-treated, mice exhibited decreased tumor burden. DSBs and tumor accumulation were pronounced in the distal colon, mirroring human CRC distribution. While ICRF-193 suppressed tumor growth, deficiency (with a compensatory TOP2α upregulation) enhanced tumor development, indicating potential roles for TOP2 isozymes in tumor formation and progression. Collectively, these findings identify the cooperative action of TOP2 and NOS2 in driving DSBs, highlighting a potential therapeutic target in inflammation-associated CRC.
Mots clés
DNA damage response, DNA topoisomerase, colitis-associated colorectal cancer, inflammation, inflammatory bowel disease, knockout mice, nitric oxide synthase
Référence
Cancers (Basel). 2026 05 8;18(10):
