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Cancer Medicine Apr 2023The prognostic value of mucinous adenocarcinomas (MCAs, exhibiting >50% extracellular mucin) of the colorectum, in relation to their anatomic location is not well...
BACKGROUND
The prognostic value of mucinous adenocarcinomas (MCAs, exhibiting >50% extracellular mucin) of the colorectum, in relation to their anatomic location is not well studied.
MATERIALS AND METHODS
We compared MCAs (n = 175) with non-MCAs (NMCAs, n = 1015) and the cancer-specific survival rates were evaluated, based on their anatomic site, by univariate Kaplan-Meier and multivariate Cox methods. Subsets of these tumors were immunostained for MUC1, MUC2, Bcl-2, and p53.
RESULTS
MCAs were more commonly found in the right colon, were of high-grade, and were more prevalent in younger patients (<40 years). They exhibited strong expression of MUC2 and Bcl-2 and showed less p53 nuclear staining. In contrast, most NMCAs were low-grade with high expression of MUC1. MCAs of the rectum were associated with poorer outcomes relative to NMCAs (HR 1.85, CI 95% 1.15-2.97), even though the distributions of advanced-stage tumors were similar.
CONCLUSION
Late-stage disease and age were poor independent prognostic indicators of cancer-specific deaths across all tumor locations. In summary, rectal MCAs have a poor prognosis.
Topics: Humans; Tumor Suppressor Protein p53; Colorectal Neoplasms; Adenocarcinoma, Mucinous; Prognosis; Mucins
PubMed: 36916704
DOI: 10.1002/cam4.5803 -
FEMS Microbiology Reviews Sep 2019A close symbiotic relationship exists between the intestinal microbiota and its host. A critical component of gut homeostasis is the presence of a mucus layer covering... (Review)
Review
A close symbiotic relationship exists between the intestinal microbiota and its host. A critical component of gut homeostasis is the presence of a mucus layer covering the gastrointestinal tract. Mucus is a viscoelastic gel at the interface between the luminal content and the host tissue that provides a habitat to the gut microbiota and protects the intestinal epithelium. The review starts by setting up the biological context underpinning the need for experimental models to study gut bacteria-mucus interactions in the digestive environment. We provide an overview of the structure and function of intestinal mucus and mucins, their interactions with intestinal bacteria (including commensal, probiotics and pathogenic microorganisms) and their role in modulating health and disease states. We then describe the characteristics and potentials of experimental models currently available to study the mechanisms underpinning the interaction of mucus with gut microbes, including in vitro, ex vivo and in vivo models. We then discuss the limitations and challenges facing this field of research.
Topics: Animals; Gastrointestinal Microbiome; Gastrointestinal Tract; Homeostasis; Host Microbial Interactions; Humans; In Vitro Techniques; Intestinal Mucosa; Mice; Microbial Interactions; Models, Animal; Mucins; Mucus; Rats
PubMed: 31162610
DOI: 10.1093/femsre/fuz013 -
Cold Spring Harbor Perspectives in... Nov 2012Our model of the MUC2 mucin shows a well-organized netlike gel that is cross-linked by six different covalent and noncovalent bonds. When the MUC2 mucin is packed in the... (Review)
Review
Our model of the MUC2 mucin shows a well-organized netlike gel that is cross-linked by six different covalent and noncovalent bonds. When the MUC2 mucin is packed in the mucin granule it is organized by an amino-terminal concatenated ring platform formed at high calcium and low pH. This packing allows an ordered release and a normal mucin expansion when calcium is removed and pH increased by bicarbonate. This process is defective in the absence of cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate transport. The expanded secreted mucin is suggested to be self-organizing by properties inherited in the MUC2 mucin and by proteolytic processes.
Topics: Bicarbonates; Gels; Glycosylation; Humans; Mucin-2; Mucins; Mucus; Polysaccharides; Protein Conformation
PubMed: 23125206
DOI: 10.1101/cshperspect.a014159 -
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 -
Biochemical Society Transactions Jun 2018In humans and mice, the first line of innate defense against inhaled pathogens and particles in the respiratory tract is airway mucus. The primary solid components of... (Review)
Review
In humans and mice, the first line of innate defense against inhaled pathogens and particles in the respiratory tract is airway mucus. The primary solid components of the mucus layer are the mucins MUC5AC and MUC5B, polymeric glycoproteins whose changes in abundance and structure can dramatically affect airway defense. Accordingly, and are tightly regulated at a transcriptional level by tissue-specific transcription factors in homeostasis and in response to injurious and inflammatory triggers. In addition to modulated levels of mucin gene transcription, translational and post-translational biosynthetic processes also exert significant influence upon mucin function. Mucins are massive macromolecules with numerous functional domains that contribute to their structural composition and biophysical properties. Single MUC5AC and MUC5B apoproteins have molecular masses of >400 kDa, and von Willebrand factor D-like as well as other cysteine-rich domain segments contribute to mucin polymerization and flexibility, thus increasing apoprotein length and complexity. Additional domains serve as sites for O-glycosylation, which increase further mucin mass several-fold. Glycosylation is a defining process for mucins that is specific with respect to additions of glycans to mucin apoprotein backbones, and glycan additions influence the physical properties of the mucins via structural modifications as well as charge interactions. Ultimately, through their tight regulation and complex assembly, airway mucins follow the biological rule of 'form fits function' in that their structural organization influences their role in lung homeostatic mechanisms.
Topics: Animals; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Lung; Mucins; Transcription, Genetic
PubMed: 29802217
DOI: 10.1042/BST20170455 -
Journal of the American Chemical Society Aug 2023Mucin glycoproteins are the major component of mucus and are integral to the cellular glycocalyx. Mucins play diverse roles in health and disease, are an important...
Mucin glycoproteins are the major component of mucus and are integral to the cellular glycocalyx. Mucins play diverse roles in health and disease, are an important element in epithelial tissue models, and have broad therapeutic potential. All mucin applications are currently challenged by their inherent structural heterogeneity and degradation by proteases. In this study, we describe the synthesis and study of chemically defined mucin analogues bearing native glycans. We utilized combinations of enantiomer amino acids and glycan thioether linkages to achieve tunable proteolysis while maintaining cytocompatibility and binding activity. Structural characterization revealed a previously unknown mirror-image helix and sheds light on the molecular drivers of glycoprotein conformation. This work represents an important step toward the development of artificial mucins for biomedical applications.
Topics: Mucins; Polysaccharides; Glycoproteins; Glycocalyx; Mucus
PubMed: 37473442
DOI: 10.1021/jacs.3c03659 -
American Journal of Physiology.... Jun 2023Mucin -linked glycans are important mediators of host-microbiota-pathogen interactions in the gastrointestinal tract. The major component of intestinal mucus, the MUC2... (Review)
Review
Mucin -linked glycans are important mediators of host-microbiota-pathogen interactions in the gastrointestinal tract. The major component of intestinal mucus, the MUC2 mucin, is densely glycosylated, with up to 80% of its weight-to-volume ratio represented by -linked glycans. Glycosylation of secretory gel-forming mucins has an enormous impact on intestinal barrier function, microbial metabolism, and mucus colonization by both pathogenic and commensal microbes. Mucin -glycans and glycan-derived sugars may be degraded and used as a nutrient source and may regulate microbial gene expression and virulence. Short-chain fatty acids, produced as a by-product of glycan fermentation, can regulate host immunity and goblet cell activity and are important for host-microbe homeostasis. Mucin glycans may also act as microbial binding sites, influencing intestinal colonization and translocation through the mucus gel barrier. Recent findings indicate that alterations to mucin glycosylation impact the susceptibility of mucins to degradation, resulting in altered barrier function and intestinal permeability. Alterations to mucin glycosylation patterns are frequently observed during intestinal infection and inflammation and have been implicated in microbiota dysbiosis and expansion of pathobionts. Recent work has demonstrated that these alterations can play key roles in disease pathogenesis. The precise mechanisms remain obscure. This review highlights the important roles of -linked glycans in host-microbe interactions and disease pathogenesis in the context of intestinal infections.
Topics: Humans; Mucins; Intestinal Mucosa; Dysbiosis; Microbiota; Host-Pathogen Interactions; Homeostasis; Polysaccharides; Mucin-2
PubMed: 37070751
DOI: 10.1152/ajpgi.00261.2022 -
Der Hautarzt; Zeitschrift Fur... Sep 2021Cutaneous mucinosis of infancy is a rare skin disease with just a few reported cases in the literature. We report the case of an 11-year-old boy with asymptomatic,...
Cutaneous mucinosis of infancy is a rare skin disease with just a few reported cases in the literature. We report the case of an 11-year-old boy with asymptomatic, skin-coloured papules and plaques on his right arm that had appeared 9 months prior to presentation. Histology showed a dermal and deep dermal interstitial mucin deposition and fibroblast proliferation. However, because cutaneous mucinosis of infancy is a benign disease with a good prognosis, therapy is not mandatory.
Topics: Child; Humans; Infant; Male; Mucin-1; Mucinoses; Mucins; Skin; Skin Diseases
PubMed: 33354742
DOI: 10.1007/s00105-020-04743-8 -
Turk Patoloji Dergisi 2023Lung adenocarcinomas are divided into acinar, lepidic, papillary, micropapillary, and solid predominant subtypes according to the current World Health Organization (WHO)...
OBJECTIVE
Lung adenocarcinomas are divided into acinar, lepidic, papillary, micropapillary, and solid predominant subtypes according to the current World Health Organization (WHO) classification. We designed this retrospective study to demonstrate profiles of MUC expression (MUC1, MUC2, MUC5AC, and MUC6) of different histologic patterns within the same tumor among pulmonary adenocarcinomas and investigate correlations of MUC expression with clinicopathologic features.
MATERIAL AND METHOD
We analyzed the expression of mucins (MUC1, MUC2, MUC5AC, and MUC6) in a series of 99 resected lung adenocarcinomas, which included a total of 193 patterns (71 acinar, 30 lepidic, 25 papillary, 20 micropapillary, 34 solid and 13 mucinous) and calculated a final immune reactivity score (FIRS) per tumor.
RESULTS
MUC1 IRS scores were significantly higher in lepidic and solid patterns compared with mucinous patterns (p=0.013). MUC2 expression was seen only in three cases (1 acinar, 2 mucinous). MUC5AC and MUC2 expression was more common in mucinous patterns (p < 0.001 and p=0.028, respectively). MUC6 expression was only detected in seven patterns and the expression was weak. No significant difference was seen among histologic patterns for the staining scores of MUC6. Mucinous adenocarcinoma differed from other histologic subtypes regarding MUC1 and MUC5AC expression. Mucinous adenocarcinoma showed less MUC1 expression with lower IRS scores and higher MUC5AC expression. Tumor size (p=0.006), lymphatic invasion (p=0.018), vascular invasion (p=0.025), perineural invasion (p=0.019), MUC1 IRS scores (p=0.018), and MUC1 IRS scores > 8.5 (p=0.018) were significant predictors for lymph node metastasis.
CONCLUSION
An alternative scoring for MUC1 can be used as a predictor for lymph node metastasis regardless of the histologic subtype.
Topics: Humans; Adenocarcinoma of Lung; Adenocarcinoma, Mucinous; Biomarkers, Tumor; Lung Neoplasms; Lymphatic Metastasis; Mucin 5AC; Mucin-1; Mucin-2; Mucin-6; Retrospective Studies
PubMed: 36367122
DOI: 10.5146/tjpath.2022.01593 -
Molecular Oncology Oct 2022Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the...
Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the mucinous subtype is known to elicit a worse response to chemotherapy and immunotherapy than the nonmucinous subtype, its pathogenesis remains poorly understood. Neurogenic locus notch homolog protein 3 (NOTCH3), a member of the NOTCH subfamilies, is highly expressed in CRC. In the past three decades, many studies have been performed evaluating the biological role of NOTCH3 in CRC. However, the precise activities of NOTCH3 in MCA, as well as the mechanisms involved in its transcriptional control, are yet to be elucidated. Our finding showed that the critical transcriptional regulatory factor transcription activator BRG1 (SMARCA4) directly binds to the intracellular domain of NOTCH3 to control transcriptional regulation. Moreover, RNA-sequencing results indicated a common targeting effect on the transcriptional activity of mucin-5AC (MUC5AC) and mucin-2 (MUC2) in CRC cells by NOTCH3 and SMARCA4. Furthermore, NOTCH3 was found to control the expressions of MUC5AC and MUC2 in a SMARCA4-dependent manner. MUC5AC and MUC2, which encode two secreted mucins, are located on chromosome 11p15.5, and are linked to the development of MCA. This finding suggests that the interaction between NOTCH3 and SMARCA4 may be involved in MCA differentiation by jointly targeting MUC5AC and MUC2. Patients with MCA are often treated in accordance with CRC guidelines. Determining the relationship between NOTCH3 and SMARCA4 by demonstrating their interactions in the pathophysiology of MCA could provide novel therapeutic targets and help identify potential prognostic markers for MCA.
Topics: Adenocarcinoma; Colorectal Neoplasms; DNA Helicases; Humans; Mucin 5AC; Mucin-2; Nuclear Proteins; RNA; Receptor, Notch3; Transcription Factors
PubMed: 35900231
DOI: 10.1002/1878-0261.13296