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

Autor:	Morrison HA; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia., Eden K; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia; Virginia Tech, Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, Virginia., Trusiano B; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia., Rothschild DE; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia., Qin Y; National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina., Wade PA; National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina., Rowe AJ; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia., Mounzer C; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia., Stephens MC; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia., Hanson KM; Via College of Osteopathic Medicine, Department of Cell Biology and Physiology, Spartanburg, South Carolina., Brown SL; Via College of Osteopathic Medicine, Department of Cell Biology and Physiology, Spartanburg, South Carolina., Holl EK; Duke University, Department of Surgery, Durham, North Carolina., Allen IC; Virginia Tech, Virginia Maryland College of Veterinary Medicine, Department of Biomedical Science and Pathobiology, Blacksburg, Virginia; Virginia Tech, Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, Virginia; Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, Virginia. Electronic address: icallen@vt.edu.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2024; Vol. 18 (3), pp. 101356. Date of Electronic Publication: 2024 May 14.
DOI:	10.1016/j.jcmgh.2024.05.004
Abstrakt:	Background & 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-kB 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 (Nik -/- ) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium. Results: Human transcriptomic data revealed dysregulated noncanonical NF-kB signaling. In vitro studies evaluating Nik -/- crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of Nik -/- cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, Nik -/- mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammation-induced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (Nik ΔCEC ). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (Nik ΔMYE ). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (RelA ΔMYE ) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (RelA ΔCEC ). 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. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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