Inflammation-Induced Tumorigenesis: Diminished Noncanonical NF-κB Signaling is Associated with Pathogenesis of Colitis-associated Colorectal Cancer

Abstract Colitis-associated colorectal cancer (CAC) is mediated by inflammation-induced tumorigenesis, causing DNA damage in susceptible cell populations. Dysregulation of inflammatory pathways in the colon is attributed to cancer pathogenesis and such signaling is attributed to NF-κB signaling. Transcription factor NF-κB is the master regulator of gene transcription and is activated through one of two pathways. Our focus is on the understudied noncanonical NF-κB signaling pathway, including NF-κB inducing kinase (NIK). NIK must be stabilized for activation of this pathway. Noncanonical signaling is attributed to the production of pro-inflammatory cytokines, recruitment of immune cells, and cell proliferation. We hypothesize that this pathway maintains gut homeostasis and when dysregulated causes cell populations to become tumorigenic. The objective of this study is to validate the clinical relevance of noncanonical signaling. We observe that diminished noncanonical signaling via whole-body Nik knockout mice results in reduced stem cell marker expression, enhanced proliferative capacity, altered microbiome composition, and increased susceptibility towards inflammation-induced tumorigenesis in the colon. Using CAC mouse models, conditional knockout strains show deletion of noncanonical signaling in epithelial cells results in increased susceptibility to colorectal tumorigenesis. Likewise, human colonic biopsy samples collected from CAC patients show significantly decreased expression levels of genes related to the noncanonical NF-kB pathway. This data suggests that the noncanonical NF-κB pathway has a protective role against colorectal cancer by regulating immune system homeostasis in the GI tract.