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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,6,10]]},"abstract":"<jats:p>\n                    Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA.\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    was identified as one of the frequently mutated genes in the inflamed colorectal epithelium of patients with ulcerative colitis; however, its significance in intestinal epithelial cells during the tumorigenic process remains unknown. Therefore, we developed an\n                    <jats:italic toggle=\"yes\">\n                      Apc\n                      <jats:sup>Min\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mouse model lacking\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    in intestinal epithelia.\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    deletion significantly enhanced colon tumor growth accompanied by elevated levels of extracellular signal-regulated kinase (ERK) phosphorylation in tumor tissues. Transcriptome analysis of the tumor tissues revealed that\n                    <jats:italic toggle=\"yes\">Nfkbiz<\/jats:italic>\n                    , a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    deletion, suggesting the protective role of Regnase-1 against colon tumor growth was dependent on IL-17 signaling triggered by gut microbes. Analysis of the\n                    <jats:italic toggle=\"yes\">Nfkbiz<\/jats:italic>\n                    knockout mouse model demonstrated that the tumor-suppressive effect of\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    depended on\n                    <jats:italic toggle=\"yes\">Nfkbiz<\/jats:italic>\n                    expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated\n                    <jats:italic toggle=\"yes\">Nfkbiz<\/jats:italic>\n                    , and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    expression in colorectal cancer tissue was related to poor prognosis. Therefore,\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    represses colon tumor growth by regulating IL-17 signaling via\n                    <jats:italic toggle=\"yes\">Nfkbiz<\/jats:italic>\n                    mRNA degradation.\n                    <jats:italic toggle=\"yes\">Regnase-1<\/jats:italic>\n                    could be a potential therapeutic target in colon tumors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2500820122","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T13:38:28Z","timestamp":1748957908000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Epithelial Regnase-1 inhibits colorectal tumor growth by regulating IL-17 signaling via degradation of\n                    <i>NFKBIZ<\/i>\n                    mRNA"],"prefix":"10.1073","volume":"122","author":[{"given":"Eriko","family":"Iguchi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5233-4120","authenticated-orcid":false,"given":"Atsushi","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsumi","family":"Oe","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University","place":["Kyoto, 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