Contribution of Membrane Mucins to Tumor Progression Through Modulation of Cellular Growth Signaling Pathways

doi:10.1016/S0070-2153(06)78001-2

Current Topics in Developmental Biology

Volume 78, 2007, Pages 1-22

https://doi.org/10.1016/S0070-2153(06)78001-2 Get rights and content

Mucins are large, heavily O‐glycosylated proteins expressed by epithelial tissues. The canonical function of membrane mucins is to provide protection to vulnerable epithelia by forming a steric barrier against assault, and by contributing to the formation of protective extracellular mucin gels. The aberrant overexpression of mucins is thought to contribute to tumor progression by allowing tumor cells to evade immune recognition, and by aiding in the breakdown of cell–cell and cell–matrix contacts to facilitate migration and metastasis. Recent evidence suggests that we should now modify our thinking about mucin function by considering their roles in signaling pathways leading to cellular growth control. Here we review the markedly divergent mechanisms by which membrane mucins, specifically MUC1 and MUC4, influence pathways contributing to cellular proliferation and survival. The cytoplasmic domain of MUC1 serves as a scaffold for the assembly of a variety of signaling proteins, while MUC4 influences the trafficking and localization of growth factor receptors, and hence their responses to external stimuli. We also discuss how tumor cells exploit these mechanisms to promote their own growth and metastasis.

Section snippets

Mucin Structure, Function, and Involvement in Tumor Progression

Mucins and mucin‐like proteins comprise a family of large transmembrane or secreted glycoproteins that are commonly associated with epithelial tissues (Strous and Dekker, 1992), but are also present at the surfaces of other selected cell types. Mucins are the major glycoprotein components of the mucous layer coating the cells lining the respiratory, digestive, and urogenital tracts, and are also prominently expressed by the ocular epithelium. Mucins possess specific domains that promote their

MUC1 Contributions to Tumor Cell Growth Signaling

The membrane mucins MUC1, MUC4, and MUC20 have each been implicated in the regulation of cellular growth signaling through their interactions with growth factor receptor tyrosine kinases (RTKs). RTKs receive signals in the form of polypeptide growth factor hormones derived from nearby cells or from endocrine sources, eliciting a cellular growth response such as proliferation, differentiation, migration, or survival.

MUC4 Contributions to Tumor Cell Growth Signaling

The vast majority of biochemical studies on MUC4 have been carried out using the rat version. Rat MUC4 is a noncovalently associated heterodimeric complex composed of two subunits, ASGP1 and ASGP2, arising from a single transcript (Carraway 2001, Rossi 1996). The translated precursor is cleaved into the two subunits during transit to the cell surface. ASGP1 is heavily O‐glycosylated and contains three Ser/Thr‐rich regions, including a 50‐amino acid N‐terminal domain, the variable tandem repeat

Inhibition of Signaling by Mucins

The membrane mucin MUC20 is highly expressed in kidney, where signaling by the Met RTK in response to hepatocyte growth factor (HGF) plays a key role in tubule formation and differentiation. MUC20 and Met physically interact independent of HGF stimulation. In contrast with MUC4, which interacts with ErbB receptors to potentiate growth factor signaling, MUC20 interaction with Met selectively suppresses HGF‐stimulated MAPK (Erk) activation. While overall Met tyrosine phosphorylation is not

Perspectives

It is becoming clear that membrane mucins have evolved functions beyond simple protection of epithelial surfaces. The different membrane mucins employ a variety of mechanisms to either augment or suppress signaling pathways involved in cellular growth control. Moreover, mucin modulation of growth signaling is a theme that extends evolutionarily back to the simplest eukaryotes. While it is also clear that tumor cells can exploit these mechanisms to their advantage, so far there is no clear

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Expression Profile of CD10, BCL-2, p63, and EMA in the Normal Skin and Basal Cell Carcinomas: An Immunohistochemical Reappraisal
2022, Actas Dermo-Sifiliograficas
Basal cell carcinoma (BCC) is common cutaneous malignancy.
To examine the expression patterns of CD10, p63, BCL-2, and epithelial membrane antigen (EMA) proteins in BCC.
We used immunohistochemistry to evaluate the expression pattern of these proteins in 45 BCC specimens and their adjacent normal skin.
We found variations in the expression pattern of these proteins among normal skins and BCC. In normal skins, we found strong EMA cytoplasmic expression (adnexal structures). A strong nuclear p63 protein expression was found in basal and some suprabasal keratinocytes, external root sheath cells of the hair follicles, basal cells of the sebaceous glands, and in sweat glands.CD10 protein expression was seen in peri-adnexal mesenchymal spindle cells and myoepithelial cells of sweat glands.BCL-2 protein expression was confined to the basal cell keratinocytes, epidermal melanocytes, outer root sheath, and infundibulum of the hair follicle. In BCC, we found p63 (diffuse, strong nuclear staining), CD10 (focal, moderate cytoplasmic reactivity), and BCL-2 (focal, moderate cytoplasmic reactivity) protein expression in the neoplastic cells. BCC was consistently negative for EMA (except in areas of squamous differentiation).
There is an altered expression of these proteins in BCC. The underlying molecular mechanisms are open to further investigations.
El carcinoma basocelular (CBC) es una neoplasia cutánea común.
Examinar los patrones de expresión de las proteínas CD10, p63, BCL-2, y antígeno epitelial de la membrana (EMA) en el CBC.
Utilizamos inmunohistoquímica para evaluar el patrón de expresión de estas proteínas en 45 muestras de CBC y su piel normal adyacente.
Encontramos variaciones del patrón de expresión de estas proteínas entre las pieles normales y el CBC. En las pieles normales, observamos una fuerte expresión citoplasmática de EMA (estructuras anexiales). Se objetivó una fuerte expresión nuclear de la proteína p63 en los queratinocitos basales y algunos suprabasales, células de la vaina de la raíz externa de los folículos pilosos, células basales de las glándulas sebáceas, y glándulas sudoríparas. La expresión de la proteína CD10 se observó en las células fusiformes mesenquimales peri-anexiales y las células mioepiteliales de las glándulas sudoríparas. La expresión de la proteína BCL-2 se confinó en los queratinocitos de las células basales, melanocitos epidérmicos, vaina de la raíz externa, e infundíbulo del folículo piloso. En CBC encontramos expresión de las proteínas p63 (difusa, fuerte tinción nuclear), CD10 (reactividad citoplasmática focal y moderada) y BCL-2 (reactividad citoplasmática focal y moderada) en las células neoplásicas. CBC fue consistentemente negativo para EMA (excepto en zonas de diferenciación escamosa).
Existe una alteración de la expresión de estas proteínas en CBC, quedando abiertos los mecanismos moleculares subyacentes a investigaciones adicionales.
Membrane-associated mucins of the ocular surface: New genes, new protein functions and new biological roles in human and mouse
2020, Progress in Retinal and Eye Research
Citation Excerpt :
In the 2007 Friedenwald Award Lecture, Dr. Ilene Gipson describes the process of characterizing MAMs of the ocular surface mucosal glycocalyx, first using a monoclonal antibody developed in her lab, then using probes from other labs, as they became available (Gipson, 2007). A number of review articles have provided perspective on the field over the years, with regard to cancers and various organ systems (Apostolopoulos and McKenzie, 1994, 2017; Bafna et al., 2010; Bhavanandan, 1991; Carraway et al., 2003, 2007; Gendler and Spicer, 1995; Gendler et al., 1991; Gum, 1992; Hattrup and Gendler, 2008; Hilkens et al., 1992; Hollingsworth and Swanson, 2004; Kim, 2012; Moniaux et al., 2001; Rose, 1992; Seregni et al., 1997; Singh and Hollingsworth, 2006; Strous and Dekker, 1992; van Putten and Strijbis, 2017; Xing et al., 2000, 2001). This includes the ocular surface (Ablamowicz and Nichols, 2016; Argueso, 2013; Argueso and Gipson, 2001; Baudouin et al., 2018; Gipson, 2004, 2007; Gipson and Argueso, 2003; Gipson et al., 2004; Gipson and Inatomi, 1998; Govindarajan and Gipson, 2010; Guzman-Aranguez and Argueso, 2010; Jentoft, 1990; Mantelli and Argueso, 2008; Mantelli et al., 2013).
The mucosal glycocalyx of the ocular surface constitutes the point of interaction between the tear film and the apical epithelial cells. Membrane-associated mucins (MAMs) are the defining molecules of the glycocalyx in all mucosal epithelia. Long recognized for their biophysical properties of hydration, lubrication, anti-adhesion and repulsion, MAMs maintain the wet ocular surface, lubricate the blink, stabilize the tear film and create a physical barrier to the outside world. However, it is increasingly appreciated that MAMs also function as cell surface receptors that transduce information from the outside to the inside of the cell. A number of excellent review articles have provided perspective on the field as it has progressed since 1987, when molecular cloning of the first MAM was reported. The current article provides an update for the ocular surface, placing it into the broad context of findings made in other organ systems, and including new genes, new protein functions and new biological roles. We discuss the epithelial tissue-equivalent with mucosal differentiation, the key model system making these advances possible. In addition, we make the first systematic comparison of MAMs in human and mouse, establishing the basis for using knockout mice for investigations with the complexity of an in vivo system. Lastly, we discuss findings from human genetics/genomics, which are providing clues to new MAM roles previously unimagined. Taken together, this information allows us to generate hypotheses for the next stage of investigation to expand our knowledge of MAM function in intracellular signaling and roles unique to the ocular surface.
MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps
2017, Journal of Allergy and Clinical Immunology
Current evidence suggests that membrane-tethered mucins could mediate corticosteroid efficacy, interacting with glucocorticoid receptor (GR) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Mucin 4 (MUC4)–tethered mucin is expressed in nasal polyp (NP) epithelial cells and upregulated under inflammatory conditions. Moreover, MUC4β has the capacity to interact with other intracellular proteins. We hypothesized that MUC4 modulates corticosteroid efficacy of patients with CRSwNP.
We sought to analyze the role of MUC4 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved.
Eighty-one patients with CRSwNP took oral corticosteroids for 15 days. Corticosteroid resistance was evaluated by using nasal endoscopy. Expression of MUC4 and MUC4β was evaluated by means of real-time PCR, Western blotting, and immunohistochemistry. BEAS-2B knockdown with RNA interference for MUC4 (small interfering RNA [siRNA]–MUC4) was used to analyze the role of MUC4 in the anti-inflammatory effects of dexamethasone.
Twenty-two patients had NPs resistant to oral corticosteroids. MUC4 expression was upregulated in these patients. In siRNA-MUC4 BEAS-2B airway epithelial cells dexamethasone produced higher anti-inflammatory effects, increased inhibition of phospho–extracellular signal-regulated kinase 1/2, increased mitogen-activated protein kinase phosphatase 1 expression, and increased glucocorticoid response element activation. Immunoprecipitation and immunofluorescence experiments revealed that MUC4β forms a complex with GRα in the nuclei of NP epithelial cells from corticosteroid-resistant patients.
MUC4β participates in the corticosteroid resistance process, inhibiting normal GRα nuclear function. The high expression of MUC4 in patients with CRSwNP might participate in corticosteroid resistance.
Ocular Surface Membrane-Associated Mucins
2016, Ocular Surface
Citation Excerpt :
In pulmonary diseases such as asthma, lung biopsies have shown increased expression of MUC4.98 Overexpression of MUC4 occurs in lung, pancreas, and breast cancers, with high levels of MUC4 indicating poor prognosis and metastasis.99 On the ocular surface, although a decrease in both conjunctival mRNA expression and tear content of MUC5AC was found in patients with Sjögren syndrome dry eye compared to normal, there was not a statistically significant difference in MUC4 conjunctival mRNA expression.34
Ocular surface epithelial cells produce and secrete mucins that form a hydrophilic barrier for protection and lubrication of the eye. This barrier, the glycocalyx, is formed by high molecular weight heavily glycosylated membrane-associated mucins (MAMs) that include MUC1, MUC4, and MUC16. These mucins extend into the tear film from the anterior surfaces of the conjunctiva and cornea, and, through interactions with galectin-3, prevent penetrance of pathogens into the eye. Due primarily to the glycosylation of the mucins, the glycocalyx also creates less friction during blinking and enables the tear film to maintain wetting of the eye. The secretory mucins include soluble MUC7 and gel-forming MUC5AC. These mucins, particularly MUC5AC, assist with removal of debris from the tear film and contribute to the hydrophilicity of the tear film. While new methodologies and cell culture models have expanded our understanding of mucin structure and function on the ocular surface, there is still a paucity of studies characterizing the glycosylation of MAMs on a normal ocular surface and a diseased ocular surface. Although studies have shown alterations in mucin production and expression in dry eye diseases, the relationship between changes in mucins and functional consequences is unclear. This review focuses on comparing what is known about MAMs in wet-surfaced epithelia of the body to what has been studied on the eye.
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The crucial role of GALNT in ovarian cancer has been demonstrated in previous studies. Previous studies demonstrated a high expression of O-glycosylated proteins, one of the prominent characteristics of ovarian carcinoma cells, is associated with cell migration, which would be attributed to the upregulated expression of glycosyltransferases [41]. Recently, Wang et al. showed that knockdown of GALNT14 by small interfering RNA significantly suppressed the cell migration and altered cellular morphology [12].
Increasing evidence has suggested that dysregulation of microRNAs (miRNAs) could contribute to tumor progression. The miR-125a was downregulated in several types of cancer, however, the molecular mechanism of miR-125a in the ovarian cancer remains unclear. The aim of the paper was to reveal the mechanism of miR-125a regulating cell proliferation and metastasis in ovarian cancer. In this study, western blotting, immunohistochemistry and serum-ELISA assay revealed that polypeptide N-acetylgalactosaminyl transferase 14 (GALNT14) expression was upregulated and correlated with the cancer stage in ovarian cancer. The expression levels of miR-125a were downregulated and negatively related to GALNT14 expression in clinical ovarian cancer tissues. Moreover, luciferase reporter assay identified polypeptide N-acetylgalactosaminyl transferase 14 (GALNT14) as a direct target of miR-125a, and overexpression of miR-125a markedly reduced the expression of GALNT14 in ovarian cancer. Functional characterization of miR-125a was accomplished by reconstitution of miR-125a and silencing GALNT14 expression in ovarian cancer cells to determine changes in proliferation and invasion. The MTT assay and transwell assay revealed that miR-125a transfectant significantly inhibits cell proliferation and invasion, by repressing GALNT14 expression. Furthermore, the gelatin zymography assay miR-125a mimics and GALNT14 siRNA suppressed the activity of MMP2 and MMP9. Taken together, our findings show that miR-125a functions as tumor suppressor in ovarian cancer by targeting GALNT14, and miR-125a may therefore serve as a biomarker for diagnosis and therapeutics in ovarian cancer.
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Glycosylation is a frequent post-translational modification which results in the addition of carbohydrate determinants, “glycans”, to cell surface proteins and lipids. These glycan structures form the “glycome” and play an integral role in cell–cell and cell–matrix interactions through modulation of adhesion and cell trafficking.
Glycosylation is increasingly recognized as a modulator of the malignant phenotype of cancer cells, where the interaction between cells and the tumor micro-environment is altered to facilitate processes such as drug resistance and metastasis. Changes in glycosylation of cell surface adhesion molecules such as selectin ligands, integrins and mucins have been implicated in the pathogenesis of several solid and hematological malignancies, often with prognostic implications. In this review we focus on the functional significance of alterations in cancer cell glycosylation, in terms of cell adhesion, trafficking and the metastatic cascade and provide insights into the prognostic and therapeutic implications of recent findings in this fast-evolving niche.

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Contribution of Membrane Mucins to Tumor Progression Through Modulation of Cellular Growth Signaling Pathways

Section snippets

Mucin Structure, Function, and Involvement in Tumor Progression

MUC1 Contributions to Tumor Cell Growth Signaling

MUC4 Contributions to Tumor Cell Growth Signaling

Inhibition of Signaling by Mucins

Perspectives

Curr. Biol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Cell

Cancer Cell

J. Biol. Chem.

Dev. Cell

J. Biol. Chem.

Exp. Eye Res.

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Exp. Cell Res.

Biochem. Pharmacol.

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J. Biol. Chem.

Cancer Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Cancer Lett.

J. Biol. Chem.

Biochim. Biophys. Acta

Semin. Oncol.

Muc1 affects c‐Src signaling in PyV MT‐induced mammary tumorigenesis

Oncogene

Gene expression profiling of neu‐induced mammary tumors from transgenic mice reveals genetic and morphological similarities to ErbB2‐expressing human breast cancers

Cancer Res.

Production and localization of Muc4/sialomucin complex and its receptor tyrosine kinase ErbB2 in the rat lacrimal gland

Invest. Ophthalmol. Vis. Sci.

MUC1 and the MUCs: A family of human mucins with impact in cancer biology

Crit. Rev. Clin. Lab. Sci.

MUC1 and nuclear beta‐catenin are coexpressed at the invasion front of colorectal carcinomas and are both correlated with tumor prognosis

Clin. Cancer Res.

Prognostic value of ERBB family mRNA expression in breast carcinomas

Int. J. Cancer

Mucins (MUC1 and MUC3) of gastrointestinal and breast epithelia reveal different and heterogeneous tumor‐associated aberrations in glycosylation

J. Histochem. Cytochem.

Muc4/sialomucin complex in the mammary gland and breast cancer

J. Mammary Gland Biol. Neoplasia

Cell signaling through membrane mucins

Bioessays

Genome‐wide search and identification of a novel gel‐forming mucin MUC19/Muc19 in glandular tissues

Am. J. Respir. Cell Mol. Biol.

Human MUC4 mucin cDNA and its variants in pancreatic carcinoma

J. Biochem. (Tokyo)

Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a function in T‐cell migration

Immunology

A signaling mucin at the head of the Cdc42‐ and MAPK‐dependent filamentous growth pathway in yeast

Genes Dev.

Genomic organization of MUC4 mucin gene. Towards the characterization of splice variants

Eur. J. Biochem.

Caspase‐induced proteolysis of the cyclin‐dependent kinase inhibitor p27Kip1 mediates its anti‐apoptotic activity

Oncogene