Faculty Collaboration Database

Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer. Oncogene 2016 May 19;35(20):2645-54

Date

09/15/2015

Pubmed ID

26364605

Pubmed Central ID

PMC5555307

DOI

10.1038/onc.2015.327

Scopus ID

2-s2.0-84941671033 (requires institutional sign-in at Scopus site)   59 Citations

Abstract

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.

Author List

Das S, Rachagani S, Sheinin Y, Smith LM, Gurumurthy CB, Roy HK, Batra SK

Author

Yuri M. Sheinin MD, PhD Associate Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CD3 Complex
Colitis
Colorectal Neoplasms
Disease Models, Animal
Gene Knockout Techniques
Histiocytes
Intestinal Mucosa
Male
Mice
Mice, Inbred C57BL
Mucin-4
T-Lymphocytes