Map3K14 signaling attenuates the development of colorectal cancer through activation of the non-canonical NF-κB signaling cascade

Abstract

Abstract Dysregulation of NF-κB signaling is a common feature in Colorectal Cancer (CRC). While the canonical signaling pathway is well characterized, the non-canonical NF-κB signaling cascade is understudied. Thus, we evaluated the hypothesis that non-canonical NF-κB signaling significantly modulates CRC pathogenesis. To evaluate this hypothesis, we initially conducted a meta-analysis of human gene expression data. Using this approach, we found that non-canonical NF-κB signaling is significantly down-regulated in CRC patients and the extent of pathway attenuation is correlated with disease severity. These findings were confirmed in patient biopsy specimens, where we found significantly reduced expression of ligands, receptors, regulators, and chemokines associated with non-canonical NF-κB signaling. Notably, we observed significantly reduced CCL19, CCL21, CXCL12, and CXCL13 expression in CRC patients compared to healthy controls. To gain mechanistic insight, we utilized genetically modified mice lacking the kinase Map3K14 (NIK), which is essential for non-canonical NF-κB signaling. Nik−/− mice exhibited ablation of non-canonical NF-κB signaling and significantly increased epithelial cell proliferation in the GI tract compared to wild type mice in both in vivo and in vitro studies. Together, our data defines a protective role for non-canonical NF-κB signaling in the gut during CRC and identifies a highly protective role for Map3K14 in attenuating epithelial cell proliferation.