{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:26Z","timestamp":1785410546783,"version":"3.56.0"},"reference-count":70,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["NSTC-114-2320-B-002-042, NSTC-113-2320-B-002-017, MOST 110-2634-F-002-004 and NTU-110L901401"],"award-info":[{"award-number":["NSTC-114-2320-B-002-042, NSTC-113-2320-B-002-017, MOST 110-2634-F-002-004 and NTU-110L901401"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NSTC-114-2320-B-002-042, NSTC-113-2320-B-002-017, MOST 110-2634-F-002-004 and NTU-110L901401"],"award-info":[{"award-number":["NSTC-114-2320-B-002-042, NSTC-113-2320-B-002-017, MOST 110-2634-F-002-004 and NTU-110L901401"]}],"id":[{"id":"https:\/\/ror.org\/0031khd05","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn\u2019s disease (CD), increase colorectal cancer (CRC) risk. Methods: 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. Results: In colon tissues from acute, chronic colitis and CRC mouse models and from CD patients, the biomarkers \u03b3H2AX and 53BP1pS25\/S29 of DNA breaks (mainly representing DSBs) accumulated, alongside increases in topoisomerase II (TOP2) and nitric oxide synthase 2 (NOS2). Genetic ablation of NOS2 (Nos2-\/-) or TOP2\u03b2 (Top2\u03b2f\/f) as well as pharmacological inhibition with ICRF-193 (a TOP2 inhibitor) or PTIO (a NO scavenger) reduced DSB formation and disease severity. Consistently, Nos2-\/-, 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, Top2\u03b2f\/f deficiency (with a compensatory TOP2\u03b1 upregulation) enhanced tumor development, indicating potential roles for TOP2 isozymes in tumor formation and progression. Conclusion: Collectively, these findings identify the cooperative action of TOP2 and NOS2 in driving DSBs, highlighting a potential therapeutic target in inflammation-associated CRC.<\/jats:p>","DOI":"10.3390\/cancers18101519","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T19:35:43Z","timestamp":1778528143000},"page":"1519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TOP2 and NOS2 Orchestrate the Generation of DNA Breaks to Promote Colitis Cancer Initiation"],"prefix":"10.3390","volume":"18","author":[{"given":"Ting-Kang","family":"Chang","sequence":"first","affiliation":[{"name":"Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road Section 1, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiu-Ling","family":"Li","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road Section 1, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2741-1048","authenticated-orcid":false,"given":"Anne-C\u00e9cile","family":"Brunac","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cytology, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 Avenue Ir\u00e8ne Joliot-Curie, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Jun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road Section 1, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Hsiu","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road Section 1, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-3291","authenticated-orcid":false,"given":"Pierre","family":"Brousset","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Anatomie Cytologie Pathologiques, IUCT-Oncopole, 1 Avenue Ir\u00e8ne Joliot-Curie, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Egly","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics and Cancer, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), CNRS\/INSERM\/University of Strasbourg, BP 163, Illkirch C\u00e9dex, 67404 Strasbourg, France"},{"name":"Centers for Genomics and Precision Medicine, National Taiwan University, Taipei 10055, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai-Kun","family":"Li","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road Section 1, Taipei 10051, Taiwan"},{"name":"Centers for Genomics and Precision Medicine, National Taiwan University, Taipei 10055, Taiwan"},{"name":"Advanced Biomedical Research Center, Taiwan Centers of Excellence, National Taiwan University, Taipei 10672, Taiwan"},{"name":"Development Center for Biotechnology, Taipei 11571, Taiwan"},{"name":"Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.cgh.2012.01.010","article-title":"Risk of Colorectal Cancer in Patients with Ulcerative Colitis: A Meta-analysis of Population-based Cohort Studies","volume":"10","author":"Jess","year":"2016","journal-title":"Clin. 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