MUC4 expression and localization in gastrointestinal tract and skin of human embryos

Zhang, Jin; Yasin, Mohammad; Carraway, Coralie A. Carothers; Carraway, Kermit L.

doi:10.1016/j.tice.2006.06.004

Cited by 16 publications

(15 citation statements)

References 21 publications

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“…Clearly the spatio-temporal pattern of expression of Muc4 is organ-and cell-specific. These results are in agreement with previous data in human (12) and rat (48) and confirm the dual role of MUC4, especially in the intestine, as a membrane-associated protein before cytodifferentiation and both as a membraneassociated and secreted protein (localization in secretory granules of goblet cells) after cytodifferentiation. Altogether these studies indicate that MUC4 has a spatio-temporal pattern of expression both in developing human and rodents, which corrobates its important role in cytodifferentiation in both species.…”

Section: Discussionsupporting

confidence: 93%

The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells

Jonckheere

Vincent

Perrais

et al. 2007

Journal of Biological Chemistry

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The human gene MUC4 encodes a large transmembrane mucin that is developmentally regulated and expressed along the undifferentiated pseudostratified epithelium, as early as 6.5 weeks during fetal development. Immunohistochemical analysis of Muc4 expression in developing mouse lung and gastrointestinal tract showed a different spatio-temporal pattern of expression before and after cytodifferentiation. The molecular mechanisms governing MUC4 expression during development are, however, unknown. Hepatocyte nuclear factors (HNF), forkhead box A (FOXA), GATA, and caudal-related homeobox transcription factors (TFs) are known to control cell differentiation of gut endoderm derived-tissues during embryonic development. They also control the expression of cell-and tissuespecific genes and may thus control MUC4 expression. To test this hypothesis, we studied and deciphered the molecular mechanisms responsible for MUC4 transcriptional regulation by these TFs. Experiments using small interfering RNA, cell cotransfection, and site-directed mutagenesis indicated that MUC4 is regulated at the transcriptional level by CDX-1 and -2, HNF-1␣ and -1␤, FOXA1/A2, HNF-4␣ and -4␥, and GATA-4, -5, and -6 factors in a cell-specific manner. Binding of TFs was assessed by chromatin immunoprecipitation, and gel-shift assays.Altogether, these results demonstrate that MUC4 is a target gene of endodermal TFs and thus point out an important role for these TFs in regulating MUC4 expression during epithelial differentiation during development, cancer, and repair.

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Section: Discussionsupporting

confidence: 93%

The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells

Jonckheere

Vincent

Perrais

et al. 2007

Journal of Biological Chemistry

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“…[38] Recent studies in our laboratory using the monoclonal antibody against the tandem repeat domain of human MUC4 (clone 8G7) have revealed that a weak expression of MUC4 is observed in the epidermis of nearly 37% of normal skin tissues. [39] Significantly, a moderately strong expression was observed in a small percentage (2/21) of normal skin tissues adjacent to a cutaneous malignancy.…”

Section: Expression Of Mucins In the Normal Skinmentioning

confidence: 99%

Role of mucins in the skin during benign and malignant conditions

Chakraborty¹,

Bonthu²,

Swanson³

et al. 2011

Cancer Letters

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Skin related diseases comprise a major health challenge to the practicing physician, and constitute a significant psychological, social and financial burden to the society. Further, skin cancer, especially non-melanoma skin cancer is currently the leading type of malignancy in the Western world. Given the huge burden of skin diseases, there is growing emphasis on understanding their pathophysiology, and towards their early detection. Mucins are high molecular weight O- and N-linked glycoproteins that have emerged in recent years as important molecules in maintaining health and in promoting or protecting against inflammation and cancer. They have also begun to emerge as highly specific diagnostic and prognostic markers and novel therapeutic targets in several malignant disorders. However, their role in cutaneous pathologies has remained largely obscured. The present review provides the expression patterns and proposed role of mucins in the healthy skin and various benign and malignant skin diseases. The review has immense clinical significance as the availability of highly specific reagents including monoclonal antibodies against mucins makes them extremely attractive targets for specific diagnosis and/or immunotherapy of benign and malignant cutaneous diseases.

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“…3 In humans, MUC1 is expressed at low levels in both small and large intestine, MUC3 predominantly expressed in small intestine 4 and MUC4 is found in equivalent amounts in both small and large intestine. 5 This normal distribution of mucins in the mucus layer changes during infection and intestinal inflammatory conditions such as UC and CD. 2 Several studies have looked into the expression pattern of different mucins in patient samples with inconclusive findings.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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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MUC4 expression and localization in gastrointestinal tract and skin of human embryos

Cited by 16 publications

References 21 publications

The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells

The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells

Role of mucins in the skin during benign and malignant conditions

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

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