title: Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sheinin
authors.affiliation: Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Mouse Genome Engineering Core Facility, Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Gurumurthy
authors.affiliation: Center for Digestive Disorders, Boston University School of Medicine, Boston, MA, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Roy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.|Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D003092:Colitis / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000150:complications*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006644:Histiocytes / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055264:Mucin-4 / Q000172:deficiency* / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D017252:CD3 Complex; C524659:Muc4 protein, mouse; D055264:Mucin-4