Virginia Research Day 2021

Graduate Student Research Biomedical

10 NF-kB Inducing Kinase Critical for Gastrointestinal Homeostasis: Dysregulation of Noncanonical NF-kB Pathway Implicated in Colitis-Associated Colorectal Cancer

Holly A. Morrison 1 ; Audrey Rowe 1 ; Katherine Baumgarner 2 ; Kristin Eden 1 ; Daniel Rothschild 1 ; Eda Holl 3 ; Stephan Brown 2 ; Irving C. Allen 1 Corresponding author: Hamorrison18@vt.edu

Colitis-associated colorectal cancer (CAC) is characterized by inflammation-induced carcinogenesis in the colon and rectum. Here, dysregulation of inflammatory signaling cascades, such as NF-kB signaling, drives the initiation of neoplastic transformation by increasing rates of DNA damage through ROS/RNS associated DNA breaks and SNPs, upregulating the production of proinflammatory cytokines, altering gut microbiota, and hindering DNA repair mechanisms. These harmful effects ultimately culminate to cause otherwise normal cells to have increased susceptibility to mutagenesis. Our research focuses on the understudied noncanonical NF-kB signaling pathway and how impairment of this signaling results in the formation of CAC. NF- κ B inducing kinase (NIK) is a pertinent 1Virginia-Maryland College of Veterinary Medicine 2 Via College of Osteopathic Medicine-Carolinas Campus 3 Duke University

enzyme in this signaling cascade and is required for further activation of the noncanonical NF- κ B signaling pathway. We hypothesize that dysregulated noncanonical NF-kB signaling generates a pro- tumorigenic microenvironment that induces intestinal epithelial cells (IECs) to acquire oncogenic mutations that promote de-differentiation into a stem-like state. In our research, we observe that complete knockout of the noncanonical pathway (i.e. Nik -/- ) in mice results in significant changes in large intestine phenotypes, including reduced stem cell marker expression, diminished regeneration/differentiation capacity upon inflammatory conditions, and increased susceptibility towards inflammation-induced carcinogenesis. Following this preliminary research, novel tissue-

specific knockout mice were generated to elucidate the mechanisms relating to the observed phenotypes. Translating this work to clinical relevancy, human colonic biopsy samples from colorectal cancer patients show significant downregulation of the noncanonical NF- κ B pathway. Together, this data suggests that the noncanonical NF- κ B pathway is critical for maintaining homeostasis in the GI tract and withstanding the damaging effects associated with cancer pathogenesis.

This study was funded in part by the VCOM One Health Seed Grant.

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