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While current GI-cancer risk estimation efforts are focused on sporadic GI-cancer mouse models, emerging <jats:italic>in-vivo<\/jats:italic> data on heavy-ion radiation-induced long-term GI-inflammation are indicative of a higher but undetermined risk of GI-inflammation associated cancers, such as colitis-associated cancer (CAC). Therefore, we aimed to assess radiation quality effects on colonic inflammation, colon cancer incidence, and associated signaling events using an <jats:italic>in-vivo<\/jats:italic> CAC model i.e., <jats:italic>Il10<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice. Male <jats:italic>Il10<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice (8\u201310 weeks, n = 12\/group) were irradiated with either sham, \u03b3-rays or heavy-ions (<jats:sup>28<\/jats:sup>Si or <jats:sup>56<\/jats:sup>Fe), and histopathological assessments for colitis and CAC were conducted at 2.5 months post-exposure. qPCR analysis for inflammation associated gene transcripts (<jats:italic>Ptges<\/jats:italic> and <jats:italic>Tgfb1<\/jats:italic>), and <jats:italic>in-situ<\/jats:italic> staining for markers of cell-proliferation (phospho-histone H3), oncogenesis (active-\u03b2-catenin, and cyclin D1), and inflammation (phospho-p65NF-\u03baB, iNOS, and COX2) were performed. Significantly higher colitis and CAC frequency were noted after heavy-ion exposure, relative to \u03b3 and control mice. Higher CAC incidence after heavy-ion exposure was associated with greater activation of \u03b2-catenin and NF-\u03baB signaling marked by induced expression of common downstream inflammatory (iNOS and COX2) and pro-proliferative (Cyclin D1) targets. In summary, IR-induced colitis and CAC incidence in <jats:italic>Il10<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice depends on radiation quality and display co-activation of \u03b2-catenin and NF-\u03baB signaling.<\/jats:p>","DOI":"10.1371\/journal.pone.0279771","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T18:55:51Z","timestamp":1672426551000},"page":"e0279771","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Heavy-ion radiation-induced colitis and colorectal carcinogenesis in Il10-\/- mice display co-activation of \u03b2-catenin and NF-\u03baB signaling"],"prefix":"10.1371","volume":"17","author":[{"given":"Shubhankar","family":"Suman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo-Hyun","family":"Moon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal","family":"Datta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhaskar V. 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