Oxytocin alleviated colitis and colitis-associated colorectal tumorigenesis by targeting fucosylated MUC2

Colon cancer is commonly regarded as hormone-independent. However, there have been reports suggesting the involvement of sex hormones in colon cancer development. Nevertheless, the role of hormones from the hypothalamus-hypophysis axis in colitis-associated colorectal cancer (CAC) remains uncertain. In this study, we observed a significant reduction in the expression of the oxytocin receptor (OXTR) in colon samples from both colitis and CAC patients. To investigate further, we generated mice with an intestinal epithelium cell (IEC)-specific knockout of OXTR. These mice exhibited markedly increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and DSS/Azoxymethane (AOM)-induced CAC compared to wild-type mice. Our findings indicate that OXTR depletion impaired the inner mucus of the colon epithelium. Mechanistically, oxytocin was found to regulate MUC2 maturation through B3GNT7-mediated fucosylation. Interestingly, we observed a positive correlation between B3GNT7 expression and OXTR expression in human colitis and CAC colon samples. Moreover, the administration of oxytocin significantly alleviated tumor burden. Hence, our study unveils oxytocin’s promising potential as an affordable and effective therapeutic intervention for individuals affected by colitis and CAC.