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Frontiers in Immunology 2024The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in... (Review)
Review
The Mucin (MUC) family, a range of highly glycosylated macromolecules, is ubiquitously expressed in mammalian epithelial cells. Such molecules are pivotal in establishing protective mucosal barriers, serving as defenses against pathogenic assaults. Intriguingly, the aberrant expression of specific MUC proteins, notably Mucin 1 (MUC1) and Mucin 16 (MUC16), within tumor cells, is intimately associated with oncogenesis, proliferation, and metastasis. This association involves various mechanisms, including cellular proliferation, viability, apoptosis resistance, chemotherapeutic resilience, metabolic shifts, and immune surveillance evasion. Due to their distinctive biological roles and structural features in oncology, MUC proteins have attracted considerable attention as prospective targets and biomarkers in cancer therapy. The current review offers an exhaustive exploration of the roles of MUC1 and MUC16 in the context of cancer biomarkers, elucidating their critical contributions to the mechanisms of cellular signal transduction, regulation of immune responses, and the modulation of the tumor microenvironment. Additionally, the article evaluates the latest advances in therapeutic strategies targeting these mucins, focusing on innovations in immunotherapies and targeted drugs, aiming to enhance customization and accuracy in cancer treatments.
Topics: Animals; Mucin-1; CA-125 Antigen; Mucins; Neoplasms; Immunity; Mammals; Tumor Microenvironment
PubMed: 38361923
DOI: 10.3389/fimmu.2024.1356913 -
Trends in Microbiology Jan 2022Many aspects of the mechanisms underlying the symbiosis between humans and gut microbes remain unknown and encompass some of the most intriguing questions in microbiome... (Review)
Review
Many aspects of the mechanisms underlying the symbiosis between humans and gut microbes remain unknown and encompass some of the most intriguing questions in microbiome research. An important factor in this symbiosis is the interplay between microbes and human-produced glycans in mucin and breast milk. In this Opinion paper, I propose a synergy between the structural diversity of human mucin glycans and the enzymatic repertoire of the gut microbiome. The contribution of microbes to mucosal health is discussed, and the role of breast milk glycans in mucosal colonization by microbes is explained. The use of prebiotic mucin glycans in general, and specialized infant and medical nutrition in particular, should be considered as the field of interest to modulate the microbiota and improve mucosal health.
Topics: Female; Gastrointestinal Microbiome; Humans; Infant; Microbiota; Milk, Human; Mucins; Polysaccharides
PubMed: 34217596
DOI: 10.1016/j.tim.2021.06.003 -
Essays in Biochemistry Apr 2023The gut microbiota interacts with the host through the mucus that covers and protects the gastrointestinal epithelium. The main component of the mucus are mucins,... (Review)
Review
The gut microbiota interacts with the host through the mucus that covers and protects the gastrointestinal epithelium. The main component of the mucus are mucins, glycoproteins decorated with hundreds of different O-glycans. Some microbiota members can utilize mucin O-glycans as carbons source. To degrade these host glycans the bacteria express multiple carbohydrate-active enzymes (CAZymes) such as glycoside hydrolases, sulfatases and esterases which are active on specific linkages. The studies of these enzymes in an in vivo context have started to reveal their importance in mucin utilization and gut colonization. It is now clear that bacteria evolved multiple specific CAZymes to overcome the diversity of linkages found in O-glycans. Additionally, changes in mucin degradation by gut microbiota have been associated with diseases like obesity, diabetes, irritable bowel disease and colorectal cancer. Thereby understanding how CAZymes from different bacteria work to degrade mucins is of critical importance to develop new treatments and diagnostics for these increasingly prevalent health problems. This mini-review covers the recent advances in biochemical characterization of mucin O-glycan-degrading CAZymes and how they are connected to human health.
Topics: Humans; Mucins; Gastrointestinal Microbiome; Polysaccharides; Bacteria
PubMed: 36695502
DOI: 10.1042/EBC20220121 -
Cell Oct 2020The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by...
The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.
Topics: Amino Acid Sequence; Animals; Biopolymers; Cryoelectron Microscopy; Disulfides; Female; Glycosylation; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Mice, Inbred C57BL; Models, Molecular; Mucins; Peptides; Protein Domains; Protein Multimerization; von Willebrand Factor
PubMed: 33031746
DOI: 10.1016/j.cell.2020.09.021 -
Molecules (Basel, Switzerland) Jun 2015O-Glycosylation is one of the most important posttranslational modifications of proteins. It takes part in protein conformation, protein sorting, developmental processes... (Review)
Review
O-Glycosylation is one of the most important posttranslational modifications of proteins. It takes part in protein conformation, protein sorting, developmental processes and the modulation of enzymatic activities. In vertebrates, the basics of the biosynthetic pathway of O-glycans are already well understood. However, the regulation of the processes and the molecular aspects of defects, especially in correlation with cancer or developmental abnormalities, are still under investigation. The knowledge of the correlating invertebrate systems and evolutionary aspects of these highly conserved biosynthetic events may help improve the understanding of the regulatory factors of this pathway. Invertebrates display a broad spectrum of glycosylation varieties, providing an enormous potential for glycan modifications which may be used for the design of new pharmaceutically active substances. Here, overviews of the present knowledge of invertebrate mucin-type O-glycan structures and the currently identified enzymes responsible for the biosynthesis of these oligosaccharides are presented, and the few data dealing with functional aspects of O-glycans are summarised.
Topics: Animals; Glycosylation; Invertebrates; Mucins
PubMed: 26065637
DOI: 10.3390/molecules200610622 -
G3 (Bethesda, Md.) Jul 2022Epithelia exposed to elements of the environment are protected by a mucus barrier in mammals. This barrier also serves to lubricate during organ movements and to mediate...
Epithelia exposed to elements of the environment are protected by a mucus barrier in mammals. This barrier also serves to lubricate during organ movements and to mediate substance exchanges between the environmental milieu and internal organs. A major component of the mucus barrier is a class of glycosylated proteins called Mucin. Mucin and mucin-related proteins are widely present in the animal kingdom. Mucin mis-regulation has been reported in many diseases such as cancers and ones involving the digestive and respiratory tracts. Although the biophysical properties of isolated Mucins have been extensively studied, in vivo models remain scarce for the study of their functions and regulations. Here, we characterize the Mucin-like JiangShi protein and its mutations in the fruit fly Drosophila. JiangShi is an extracellular glycoprotein with domain features reminiscent of mammalian nonmembranous Mucins, and one of the most widely distributed Mucin-like proteins studied in Drosophila. Both loss and over-production of JiangShi lead to terminal defects in adult structures and organismal death. Although the physiological function of JiangShi remains poorly defined, we present a genetically tractable model system for the in vivo studies of Mucin-like molecules.
Topics: Animals; Drosophila; Glycoproteins; Glycosylation; Mammals; Mucins; Respiratory System
PubMed: 35595239
DOI: 10.1093/g3journal/jkac126 -
World Journal of Gastroenterology Sep 2018To determine tissue expression (mRNA, protein) of two types of mucins [mucin 1 (MUC1) and mucin 2 (MUC2)] in patients with colorectal cancer (CRC). (Comparative Study)
Comparative Study
AIM
To determine tissue expression (mRNA, protein) of two types of mucins [mucin 1 (MUC1) and mucin 2 (MUC2)] in patients with colorectal cancer (CRC).
METHODS
Expression of membrane-bound mucin (MUC1) and secretory mucin (MUC2) in CRC (mRNA, protein) were analyzed in tissue material including fragments of tumors obtained from CRC patients ( = 34), and fragments of normal colorectal tissue from the same patients (control). The analysis was conducted using real-time quantitative polymerase chain reaction (RT-qPCR) (transcripts), immunohistochemistry (IHC) (apomucins), and the modern approach for morphometric analysis of IHC reaction (HSV filter software). Results on tissue expression of both mucins (mRNA, protein) were compared to histological alterations in colorectal cancer samples and correlated with selected clinical data in the patients. The statistical analysis was conducted using Statistica PL v. 12.0 software.
RESULTS
Significantly higher expression of the MUC1 mRNA in the CRC, compared with the control and the borderline correlation of mRNA expression with MUC1 protein levels in colorectal samples was observed. The expression of apomucins concerned cell membranes (MUC1) and cytoplasm (MUC2) and occurred both in control tissues and in most cancerous samples. There were no significant relationships between MUC1 (mRNA, protein) and the clinicopathological data of patients. MUC2 protein expression was significantly lower as compared to the control, while MUC2 mRNA expression was comparable in both groups. The MUC1/MUC2 ratio was significantly higher in CRC tissues than in the control. The higher expression of MUC2 was a feature of mucinous CRC subtypes, and characterized higher histological stage of tumors. Negative correlations have been obtained between MUC2 and the Ki-67 antigen, as well as between MUC2 and p53 protein expressions in CRC.
CONCLUSION
A combination of tissue overexpression of MUC1, reduced MUC2 expression, and high ratio of MUC1/MUC2 is a factor of poor prognosis in CRC patients. MUC2 tissue expression allows to differentiate mucinous and nonmucinous CRC subtypes.
Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Colorectal Neoplasms; Female; Humans; Intestine, Large; Male; Middle Aged; Mucin-1; Mucin-2; Neoplasm Staging; Prognosis; RNA, Messenger; Survival Rate
PubMed: 30271081
DOI: 10.3748/wjg.v24.i36.4164 -
Macromolecular Bioscience Aug 2017The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held... (Review)
Review
The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held in Munster on 2-3 September 2015 as a satellite event of the ICCC 13th-EUCHIS 12th. After a brief outline of the new issues, the focus is on mucus description, purification, and mucus/mucin characterization, all steps that are pivotal to the understanding of mucus related phenomena and the choice of the correct mucosal model for in vitro and ex vivo experiments, alternative bio/mucomimetic materials are also presented. Then a selection of preparative techniques and testing methods are described (at molecular as well as micro and macroscale) that may support the pharmaceutical development of mucus interactive systems and assist formulators in the scale-up and industrialization steps. Recent applications of mucoadhesive systems (including medical devices) intended for different routes of administration (oral, gastrointestinal, vaginal, nasal, ocular, and intravesical) and for the treatment of difficult to treat pathologies or the alleviation of symptoms are described.
Topics: Animals; Biomedical Research; Biomimetic Materials; Humans; Mucins; Mucus
PubMed: 28378910
DOI: 10.1002/mabi.201600534 -
Cancer Metastasis Reviews Sep 2020A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called... (Review)
Review
A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called mucins. Mucins, broadly grouped into transmembrane and secreted mucins, are the first responders to any mechanical or chemical insult to the epithelia and help maintain tissue homeostasis. However, their intrinsic properties to protect and repair the epithelia are exploited during oncogenic processes, where mucins are metamorphosed to aid the tumor cells in their malignant journey. Diverse domains, like the variable number tandem repeats (VNTR), sea urchin sperm protein enterokinase and agrin (SEA), adhesion-associated domain (AMOP), nidogen-like domain (NIDO), epidermal growth factor-like domain (EGF), and von Willebrand factor type D domain (vWD) on mucins, including MUC1, MUC4, MUC5AC, MUC5B, and MUC16, have been shown to facilitate cell-to-cell and cell-to-matrix interactions, and cell-autonomous signaling to promote tumorigenesis and distant dissemination of tumor cells. Several obstacles have limited the study of mucins, including technical difficulties in working with these huge glycoproteins, the dearth of scientific tools, and lack of animal models; thus, the tissue-dependent and domain-specific roles of mucins during mucosal protection, chronic inflammation, tumorigenesis, and hematological dissemination of malignant cells are still unclear. Future studies should try to integrate information on the rheological, molecular, and biological characteristics of mucins to comprehensively delineate their pathophysiological role and evaluate their suitability as targets in future diagnostic and therapeutic strategies.
Topics: Animals; Humans; Mucins; Neoplasm Metastasis; Neoplasms; Protein Domains
PubMed: 32488403
DOI: 10.1007/s10555-020-09896-5 -
International Journal of Molecular... Dec 2021Maintaining intestinal health requires clear segregation between epithelial cells and luminal microbes. The intestinal mucus layer, produced by goblet cells (GCs), is a... (Review)
Review
Maintaining intestinal health requires clear segregation between epithelial cells and luminal microbes. The intestinal mucus layer, produced by goblet cells (GCs), is a key element in maintaining the functional protection of the epithelium. The importance of the gut mucus barrier is highlighted in mice lacking , the major form of secreted mucins. These mice show closer bacterial residence to epithelial cells, develop spontaneous colitis and became moribund when infected with the attaching and effacing pathogen, . Furthermore, numerous observations have associated GCs and mucus layer dysfunction to the pathogenesis of inflammatory bowel disease (IBD). However, the molecular mechanisms that regulate the physiology of GCs and the mucus layer remain obscured. In this review, we consider novel findings describing divergent functionality and expression profiles of GCs subtypes within intestinal crypts. We also discuss internal (host) and external (diets and bacteria) factors that modulate different aspects of the mucus layer as well as the contribution of an altered mucus barrier to the onset of IBD.
Topics: Animals; Colitis; Epithelial Cells; Gastrointestinal Microbiome; Goblet Cells; Humans; Inflammatory Bowel Diseases; Mice; Mucins
PubMed: 34948435
DOI: 10.3390/ijms222413642