MUC4, a large transmembrane
mucin normally expressed in the small and large intestine, is differentially expressed during inflammatory and malignant conditions of the colon. However, the expression pattern and the role of MUC4 in
colitis and
colorectal cancer (CRC) are inconclusive. Therefore, the aim of this study was to understand the role of Muc4 during inflammatory and malignant conditions of the colon. Here, we generated Muc4(-/-) mice and addressed its role in
colitis and
colitis-associated CRC using
dextran sodium sulfate (DSS) and
azoxymethane (AOM)-DSS experimental models, respectively. Muc4(-/-) mice were viable, fertile with no apparent defects. Muc4(-/-) mice displayed increased resistance to DSS-induced
colitis compared with wild-type (WT) littermates that was evaluated by survival rate,
body weight loss,
diarrhea and fecal blood score, and histological score. Reduced infiltration of inflammatory cells, that is, CD3(+) lymphocytes and F4/80(+) macrophages was observed in the inflamed mucosa along with reduction in the
mRNA levels of inflammatory
cytokines interleukin (IL)-1β and
tumor necrosis factor (TNF)-α and anti-microbial genes
Lysozyme M and SLPI in the colon of Muc4(-/-) mice compared with WT littermates. Compensatory upregulation of Muc2 and Muc3
mucins under basal and DSS treatment conditions partly explains the resistance observed in Muc4(-/-) mice. Accordingly, Muc4(-/-) mice exhibited significantly reduced
tumor burden compared with WT mice assessed in a
colitis-induced
tumor model using AOM/DSS. An increased percentage of Ki67(+) nuclei was observed in the
tumors from WT compared with Muc4(-/-) mice suggesting Muc4 to be critical in intestinal cell proliferation during
tumorigenesis. Taken together, we conclusively demonstrate for the first time the role of Muc4 in driving intestinal
inflammation and
inflammation-associated
tumorigenesis using a novel Muc4(-/-) mouse model.