ELEVATED ADENOMATOUS POLYPOSIS COLI IN GOBLET CELLS IS ASSOCIATED WITH INFLAMMATION IN MOUSE AND HUMAN COLON

Abstract

Abstract Adenomatous Polyposis Coli (APC) functions as an essential colon tumor suppressor. Roles for APC in other disease states such as Inflammatory Bowel Disease (IBD) remain less defined. In the process of characterizing Apc protein in gastrointestinal tissues from human patients with active IBD, we found a subset of goblet cells with elevated Apc staining intensity. While normal colon tissue was only sparsely populated with these “APChigh” goblet cells, tissue from patients with Ulcerative Colitis and Crohn’s Disease contained entire regions where almost every goblet cell was APChigh. In the descending colon, the APChigh goblet cells were prominent in patients with active Ulcerative Colitis but were mostly lacking in normal samples. In mice, APChigh cells were observed only in the small intestines and proximal/medial colons. Upon induction of colitis with Dextran Sodium Sulfate (DSS), the APChigh goblet cells remained in the proximal and medial colon, but also appeared in the distal colon. To better understand the link between APC expression, goblet cells, and inflammation, cultured human colon cells derived from normal tissue were depleted of APC and RNAseq analysis was performed. APC depletion resulted in reduced expression of mRNAs encoding IL1 signaling pathway components IL1b and IL1R, known regulators of Muc2 expression. Muc2 is the main constituent of goblet cell mucus, which is secreted to form a protective barrier for the epithelial cells lining the large intestine. We found that treating cancer cells lacking wild-type APC with IL1b resulted in increased IL1R and MUC2 expression. Induction of full-length APC in these cells led to a similar phenotype. Combining IL1β treatment with APC induction led to an increase of MUC2 expression greater than expected for additive affects, suggesting that APC sensitized these cells to IL1 signaling. These results illuminate a novel role for APC in goblet cells under conditions of inflammation. We postulate that the higher amount of APC in a subset of goblet cells might sensitize them to IL-1 signaling. During times of inflammation, such as active Ulcerative Colitis, goblet cells with higher APC levels would be more sensitive to IL-1-induced MUC2 expression than other goblet cells, perhaps protecting the intestinal lining from further barrier breaches.