Patients with inflammatory bowel disease (IBD) have an increased risk of developing colitis-associated colon cancer (CACC). Despite the strong relationship between inflammation and cancer, the mechanistic events that contribute to the transition from IBD to CACC remain undefined. Changes in the glycosylation profile of the known oncoprotein MUC1 commonly occur in chronic inflammation and may facilitate progression to cancer. We used a transwell coculture model system to examine the effect of polarized macrophages, such as those contributing to inflammation, on the expression of glycosylation-related enzymes in colon cancer cells. We found that M2-like macrophages induce the expression of ST6GALNAC1 glycosyltransferase which, by adding sialic acid to O-linked GalNAc residues, promotes the formation of the tumor-associated MUC1-sTn glycoform. Cytokine antibody arrays and blocking antibody experiments revealed that high levels of IL-13 and CCL17, present in the conditioned medium of colon cells cocultured with M2 macrophages, activate ST6GALNAC1 expression in colon cancer cells. In silico and in vivo murine and human models of colitis and CACC showed that IL-13 induces the phosphorylation of STAT-6 that directly binds ST6GALNAC1 promoter resulting in its transcription activation and protein over-expression. On the other hand, CCL17 activates ST6GALNAC1 expression via NF-kB pathway signaling. Our findings revealed a novel cross-talk between M2-like macrophages and inflamed and malignant colon cells that contributes to the pathogenesis of colitis and progression to CACC.
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