Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer

Abstract

Patients with ulcerative colitis have an increased risk of developing colitis-associated colon cancer (CACC). Changes in glycosylation of the oncoprotein MUC1 commonly occur in chronic inflammation, including ulcerative colitis, and this abnormally glycosylated MUC1 promotes cancer development and progression. It is not known what causes changes in glycosylation of MUC1. Gene expression profiling of myeloid cells in inflamed and malignant colon tissues showed increased expression levels of inflammatory macrophage–associated cytokines compared with normal tissues. We analyzed the involvement of macrophage-associated cytokines in the induction of aberrant MUC1 glycoforms. A coculture system was used to examine the effects of M1 and M2 macrophages on glycosylation-related enzymes in colon cancer cells. M2-like macrophages induced the expression of the glycosyltransferase ST6GALNAC1, an enzyme that adds sialic acid to O-linked GalNAc residues, promoting the formation of tumor-associated sialyl-Tn (sTn) O-glycans. Immunostaining of ulcerative colitis and CACC tissue samples confirmed the elevated number of M2-like macrophages as well as high expression of ST6GALNAC1 and the altered MUC1-sTn glycoform on colon cells. Cytokine arrays and blocking antibody experiments indicated that the macrophage-dependent ST6GALNAC1 activation was mediated by IL13 and CCL17. We demonstrated that IL13 promoted phosphorylation of STAT6 to activate transcription of ST6GALNAC1. A computational model of signaling pathways was assembled and used to test IL13 inhibition as a possible therapy. Our findings revealed a novel cellular cross-talk between colon cells and macrophages within the inflamed and malignant colon that contributes to the pathogenesis of ulcerative colitis and CACC. See related Spotlight on p. 160

Bioinformatics Analysis of Differentially Expressed Genes and Protein–Protein Interaction Networks Associated with Functional Pathways in Ulcerative Colitis

“…UC is recurrent and difficult to heal, and it is referred to as “deathless cancer” due to its serious impact on patients’ quality of life. UC is closely related to the development of colon cancer [ 5 ], which is difficult to cure. The pathogenesis of UC has not been clarified, and the possible underlying mechanisms include bacterial infection, intestinal mucosal barrier dysfunction, and genetic, dietary, environmental, immunological, and psychological factors [ 6 ].…”

miR‑31 promotes tumorigenesis in ulcerative colitis‑associated neoplasia via downregulation of SATB2

“…The frequency of inflammation-associated microsatellite alterations was increased during the progression of UCAN (23). Glycosyltransferase ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1) was induced by M2-like macrophages, and ST6Galnac1 alters the glycosylation status of the oncoprotein mucin 1, thereby promoting cancer development and progression in UC (24). However, the exact mechanisms underlying the pathogenesis of UCAN remain elusive.…”

Lymphocyte infiltration and key differentially expressed genes in the ulcerative colitis

“…UC was an incurable and recurrent IBD disease, that eventually could progress to colon cancer. [ 3 ] Although a large number of studies had demonstrated that it was related to many factors, such as genes, environment, immunity, and infection, its exact etiology had not been clearly elucidated so far. [ 1 ] The histopathology showed that lots of immune cells would infiltrate in the mucosal layer of the intestinal wall, such as neutrophils, macrophages, dendritic cells, and T lymphocytes, etc.…”

“…[ 2 ] UC was sometimes difficult to cure, it was easy to relapse, and then the patients could form polyps, even malignant turn into colon cancer. [ 3 ] Epidemiology showed that the incidence of UC was increasing year by year globally. [ 4 ] It was widespread in 20 to 40 years old adults, and there was no gender difference.…”