NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Q1 Regeneration

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dc.contributor.authorMorrison, Holly A.en
dc.contributor.authorEden, Kristinen
dc.contributor.authorTrusiano, Brieen
dc.contributor.authorRothschild, Daniel E.en
dc.contributor.authorQin, Yufengen
dc.contributor.authorWade, Paul A.en
dc.contributor.authorRowe, Audrey J.en
dc.contributor.authorMounzer, Christinaen
dc.contributor.authorStephens, Morgan C.en
dc.contributor.authorHanson, Katherine M.en
dc.contributor.authorBrown, Stephan L.en
dc.contributor.authorHoll, Eda K.en
dc.contributor.authorAllen, Irving C.en
dc.date.accessioned2024-07-11T17:45:45Zen
dc.date.available2024-07-11T17:45:45Zen
dc.date.issued2024-06en
dc.description.abstractBACKGROUND & AIMS: Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-𝜅B-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/ differentiation via noncanonical NF-𝜅B signaling that is unique from canonical NF-𝜅B signaling. METHODS: Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis were initiated in whole-body NIK knockout mice (<i>Nik</i>⁻/⁻) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium. RESULTS: Human transcriptomic data revealed dysregulated noncanonical NF-𝜅B signaling. In vitro studies evaluating <i>Nik</i>⁻/⁻ crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of <i>Nik</i>⁻/⁻ cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, <i>Nik</i>⁻/⁻ mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammationinduced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (<i>Nik<sup>ΔCEC</sup></i>). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (<i>Nik<sup>ΔMYE</sup></i>). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (<i>RelA<sup>ΔMYE</sup></i>) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (<i>RelA<sup>ΔCEC</sup></i>) CONCLUSIONS: Dysregulated noncanonical NF-𝜅B signaling is associated with the development of colorectal cancer in a tissue-dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.en
dc.description.sponsorshipSupported by the NIH (R03DK105975; NCATS iTHRIVE UL1TR003015), The Virginia-Maryland College of Veterinary Medicine, The Via College of Osteopathic Medicine, and The Virginia Tech Carilion School of Medicine.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.jcmgh.2024.05.004en
dc.identifier.issue3en
dc.identifier.urihttps://hdl.handle.net/10919/120647en
dc.identifier.volume18en
dc.language.isoenen
dc.publisherElsevieren
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectColitis-Associated Tumorigenesisen
dc.subjectDifferentiationen
dc.subjectOrganoidsen
dc.subjectEpithelial cellsen
dc.titleNF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Q1 Regenerationen
dc.title.serialCellular and Molecular Gastroenterology and Hepatologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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