{"doi":"10.1016/j.jcmgh.2024.05.004","title":"NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Regeneration","abstract":"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.","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2024,"id":428171,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9712,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":497989,"name":"Kristin Eden","orcid":"0000-0001-5309-5830","position":1,"is_corresponding":false},{"id":1229360,"name":"Brie Trusiano","orcid":"0000-0003-4258-7463","position":2,"is_corresponding":false},{"id":1229846,"name":"Daniel E. Rothschild","orcid":null,"position":3,"is_corresponding":false},{"id":307410,"name":"Yufeng Qin","orcid":"0000-0002-3947-7610","position":4,"is_corresponding":false},{"id":247177,"name":"Paul A. Wade","orcid":"0000-0002-6042-357X","position":5,"is_corresponding":false},{"id":1229847,"name":"Audrey J. Rowe","orcid":null,"position":6,"is_corresponding":false},{"id":1229848,"name":"Christina Mounzer","orcid":null,"position":7,"is_corresponding":false},{"id":1229849,"name":"Morgan C Stephens","orcid":null,"position":8,"is_corresponding":false},{"id":1229361,"name":"Katherine M. Hanson","orcid":"0000-0003-3872-1500","position":9,"is_corresponding":false},{"id":412752,"name":"Stephan Brown","orcid":null,"position":10,"is_corresponding":false},{"id":374165,"name":"Eda K. Holl","orcid":"0000-0002-6975-3647","position":11,"is_corresponding":false},{"id":297448,"name":"Irving C. Allen","orcid":"0000-0001-9573-5250","position":12,"is_corresponding":false},{"id":628657,"name":"Holly A. Morrison","orcid":"0000-0001-7358-7728","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T01:58:57.592578Z","pmid":"38750899","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}