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.

Original languageEnglish (US)
Pages (from-to)2645-2654
Number of pages10
JournalOncogene
Volume35
Issue number20
DOIs
StatePublished - May 19 2016

Fingerprint

Colitis
Colorectal Neoplasms
Dextran Sulfate
Azoxymethane
Colon
Mucins
Carcinogenesis
Microbial Genes
Inflammation
Large Intestine
Muramidase
Tumor Burden
Interleukin-1
Small Intestine
Weight Loss
Diarrhea
Neoplasms
Mucous Membrane
Theoretical Models
Up-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

@article{f9556390a5ab4a719987cc484bdf8566,
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.",
author = "S. Das and Satyanarayana Rachagani and Y. Sheinin and Smith, {Lynette M} and Gurumurthy, {Channabasavaiah B} and Roy, {H. K.} and Batra, {Surinder Kumar}",
year = "2016",
month = "5",
day = "19",
doi = "10.1038/onc.2015.327",
language = "English (US)",
volume = "35",
pages = "2645--2654",
journal = "Oncogene",
issn = "0950-9232",
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TY - JOUR

T1 - Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer

AU - Das, S.

AU - Rachagani, Satyanarayana

AU - Sheinin, Y.

AU - Smith, Lynette M

AU - Gurumurthy, Channabasavaiah B

AU - Roy, H. K.

AU - Batra, Surinder Kumar

PY - 2016/5/19

Y1 - 2016/5/19

N2 - 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.

AB - 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.

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