Abstract 5214: Nuclear APC maintains colon homeostasis and mitigates inflammation

Abstract Adenomatous polyposis coli (APC) is critical for maintaining intestinal homeostasis. Although widely recognized for its cytoplasmic tumor suppressor functions, the roles of APC in other subcellular compartments and inflammation are less defined. To investigate nuclear APC functions, we developed a mouse model with compromised nuclear Apc import (ApcmNLS/mNLS mice). ApcmNLS/mNLS mice displayed lower levels of mucin-2 (MUC2) RNA, the primary component of the intestinal mucus barrier, and had significantly thinner colonic mucus layers. These mice were more susceptible to experimentally induced colitis than their wild-type littermates. Importantly, male ApcmNLS/mNLS mice exhibited significantly increased weight loss and higher colitis scores compared to female mice. Therefore, we hypothesize that nuclear APC promotes gut barrier integrity by upregulating MUC2 expression. In cultured human colon cells, APC positively regulates MUC2 RNA levels and inhibits NF-κB signaling. Overall, this study provides evidence that nuclear APC upregulates colonic MUC2 expression, increases the mucus barrier, and inhibits colonic inflammation. Furthermore, our results reveal notable sex-specific differences in colitis susceptibility. Citation Format: Anika James, Kristi Neufeld. Nuclear APC maintains colon homeostasis and mitigates inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5214.