Tissue-specific pools of Selenoprotein P differentially contribute to colitis-associated carcinogenesis

Patients with inflammatory bowel disease demonstrate nutritional Se deficiencies and are at increased risk for colon cancer due to heightened inflammation and oxidative stress. Previously, we determined that global loss of the selenium-containing protein, Selenoprotein P (SELENOP), exacerbates experimental colitis-associated cancer (CAC). This was likely due to antioxidant function, as heighted tumorigenesis was also observed in mice expressing a redox-deficient SELEOP mutant. However, because SELENOP loss altered both immune and epithelial cellular function, we sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis. Conditional Selenop floxed mice were crossed with Albumin-Cre, Villin-CreER, or LysM-Cre lines to drive Selenop loss in the liver, intestinal epithelium, or myeloid lineage, respectively. Resulting cohorts were placed on an azoxymethane/dextran sodium sulfate (AOM/DSS) experimental CAC protocol. Although liver-specific Selenop deletion decreased levels of colonic Se, it failed to modify AOM/DSS-mediated tumorigenesis. Myeloid-specific Selenop deletion was observed to induce modest effects on macrophage function, as it decreased migration, promoted M1 polarization, and induced Nos2 expression. However, LysM-Cre; Selenop fl/fl mice showed no alteration in tumor number over LysM-Cre; Selenop WT controls. Instead, only epithelial-specific deletion increased tumor incidence, number, size, and degree of dysplasia in the CAC model. Tumors were also observed to have increased amounts of DNA damage, suggesting increased tumor formation was due to heightened oxidative stress. Interestingly, unlike the Selenop global model, no effect was observed with heterozygous epithelial-specific loss. Despite the vast majority of total body SELENOP being produced by the liver, these results implicate locally-expressed SELENOP as the primary mediator of disease severity. As epithelial-specific loss increased DNA damage and apoptosis, this pool of SELENOP likely attenuates tumor initiation through antioxidant mechanisms. However, these results still differed from those seen with global Selenop loss, suggesting additional SELENOP pools may yet contribute to protection against inflammatory-carcinogenesis.