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

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.

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.

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).

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.