-
The Journal of Clinical Investigation Oct 2023The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the...
The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and noninflamed samples from patients with inflammatory bowel disease (IBD) undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF/CFTR signaling axis in the adult intestine and identify epithelial cell-derived TNF as an upstream regulator of mucin homeostasis.
Topics: Humans; Animals; Mice; Mucins; Cystic Fibrosis Transmembrane Conductance Regulator; Tumor Necrosis Factor Inhibitors; Epithelial Cells; Cell Differentiation; Tumor Necrosis Factors; Homeostasis
PubMed: 37643009
DOI: 10.1172/JCI163591 -
Molecules (Basel, Switzerland) Oct 2023Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the... (Review)
Review
Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the human body, which can be classified into secreted mucins and transmembrane mucins according to their distributions. The major difference between them is that secreted mucins do not have transmembrane structural domains, and the expression of each mucin is organ and cell-specific. Under physiological conditions, mucin glycans are involved in the composition of the mucus barrier and thus protect the body from infection and injury. However, abnormal expression of mucin glycans can lead to the occurrence of diseases, especially cancer, through various mechanisms. Therefore, targeting mucin glycans for the diagnosis and treatment of cancer has always been a promising research direction. Here, we first summarize the main types of glycosylation (O-GalNAc glycosylation and N-glycosylation) on mucins and the mechanisms by which abnormal mucin glycans occur. Next, how abnormal mucin glycans contribute to cancer development is described. Finally, we summarize MUC1-based antibodies, vaccines, radio-pharmaceuticals, and CAR-T therapies using the best characterized MUC1 as an example. In this section, we specifically elaborate on the recent new cancer therapy CAR-M, which may bring new hope to cancer patients.
Topics: Humans; Mucins; Mucin-1; Polysaccharides; Glycosylation; Neoplasms
PubMed: 37894512
DOI: 10.3390/molecules28207033 -
Cancers Jun 2023Appendiceal mucinous neoplasms have been classified differently over time causing confusion when comparing results between working groups in this field and establishing... (Review)
Review
Appendiceal mucinous neoplasms have been classified differently over time causing confusion when comparing results between working groups in this field and establishing a prognosis of the disease. A historical perspective of the different classification systems of these tumors is essential for the understanding of the evolution of concepts and histopathological definitions that have led up to the present moment. We carried out a systematic review of the pathological classifications of appendiceal mucinous tumors and how they have included the new criteria resulting from clinical and pathological research. The latest classifications by PSOGI and AJCC 8th edition Cancer Staging have made a great effort to incorporate the new pathological descriptions and develop prognostic groups. The introduction of these new classification systems has posed the challenge of verifying how they adapt to our casuistry and which one defines best the prognosis of our patients. We reclassified our series of patients treated for mucinous appendiceal tumors with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy following the PSOGI and the AJCC 8th edition criteria and concluded that both classifications correspond well with the OS and DFS of these patients, with some advantage relative to the PSOGI classification due to a better histopathological description of the different groups.
PubMed: 37444536
DOI: 10.3390/cancers15133426 -
Heliyon Aug 2023Mucinous ovarian carcinoma (MOC) is a rare histological type of epithelial ovarian cancer. It has poor response to conventional platinum-based chemotherapy regimens and... (Review)
Review
Mucinous ovarian carcinoma (MOC) is a rare histological type of epithelial ovarian cancer. It has poor response to conventional platinum-based chemotherapy regimens and PARPi-based maintenance treatment, resulting in short survival and poor prognosis in advanced-disease patients. MOC is characterized by mucus that is mainly composed of mucin in the cystic cavity. Our review discusses in detail the role of mucins in MOC. Mucins are correlated with MOC development. Furthermore, they are valuable in the differential diagnosis of primary and secondary ovarian mucinous tumors. Some types of mucins have been studied in the context of chemoresistance and targeted therapy for ovarian cancer. This review may provide a new direction for the diagnosis and treatment of advanced MOC.
PubMed: 37664708
DOI: 10.1016/j.heliyon.2023.e19221 -
Life Science Alliance Sep 2023The interplay between genetic and environmental factors influences the course of chronic kidney disease (CKD). In this context, genetic alterations in the kidney disease...
The interplay between genetic and environmental factors influences the course of chronic kidney disease (CKD). In this context, genetic alterations in the kidney disease gene (Mucin1) predispose to the development of CKD. These variations comprise the polymorphism rs4072037, which alters splicing of MUC1 mRNA, the length of a region with variable number of tandem repeats (VNTR), and rare autosomal-dominant inherited dominant-negative mutations in or 5' to the VNTR that causes autosomal dominant tubulointerstitial kidney disease (ADTKD-). As hypoxia plays a pivotal role in states of acute and chronic kidney injury, we explored the effects of hypoxia-inducible transcription factors (HIF) on the expression of and its pathogenic variants in isolated primary human renal tubular cells. We defined a HIF-binding DNA regulatory element in the promoter-proximal region of from which hypoxia or treatment with HIF stabilizers, which were recently approved for an anti-anemic therapy in CKD patients, increased levels of wild-type and the disease-associated variants. Thus, application of these compounds might exert unfavorable effects in patients carrying risk variants.
Topics: Humans; Kidney; Polycystic Kidney Diseases; Hypoxia; Disease Progression; Renal Insufficiency, Chronic; Mucin-1
PubMed: 37316299
DOI: 10.26508/lsa.202302078 -
Science Advances Oct 2023Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the...
Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the intestinal epithelium is well appreciated, the direct effect of BMP on intestinal stromal cells is poorly understood. Here, we show that disruption of BMP signaling by genetic ablation of or expands the stromal cell pool, the mucosa tumefaction, and colonic polyposis in the large intestine. Interleukin (IL) secretion by stromal cells is notably increased, including IL-1, IL-11, and IL-17. Specifically, IL-1 and IL-17a hyperactivate the mucin production by goblet cells through nuclear factor κB signaling, and abnormal mucin accumulation results in the morphological changes, epithelial barrier destruction, and polyposis development. Together, our results provide an insight into the role of BMP signaling in intestinal stromal cells to regulate epithelium function. This study further highlights the role of mucin-producing goblet cells in intestinal homeostasis and colitis development.
Topics: Humans; Mucins; Interleukin-17; Signal Transduction; Colorectal Neoplasms; Interleukin-1
PubMed: 37889976
DOI: 10.1126/sciadv.adi1827 -
PLoS Pathogens Aug 2023Mucins play an essential role in protecting the respiratory tract against microbial infections while also acting as binding sites for bacterial and viral adhesins. The...
Mucins play an essential role in protecting the respiratory tract against microbial infections while also acting as binding sites for bacterial and viral adhesins. The heavily O-glycosylated gel-forming mucins MUC5AC and MUC5B eliminate pathogens by mucociliary clearance. Transmembrane mucins MUC1, MUC4, and MUC16 can restrict microbial invasion at the apical surface of the epithelium. In this study, we determined the impact of host mucins and mucin glycans on epithelial entry of SARS-CoV-2. Human lung epithelial Calu-3 cells express the SARS-CoV-2 entry receptor ACE2 and high levels of glycosylated MUC1, but not MUC4 and MUC16, on their cell surface. The O-glycan-specific mucinase StcE specifically removed the glycosylated part of the MUC1 extracellular domain while leaving the underlying SEA domain and cytoplasmic tail intact. StcE treatment of Calu-3 cells significantly enhanced infection with SARS-CoV-2 pseudovirus and authentic virus, while removal of terminal mucin glycans sialic acid and fucose from the epithelial surface did not impact viral entry. In Calu-3 cells, the transmembrane mucin MUC1 and ACE2 are located to the apical surface in close proximity and StcE treatment results in enhanced binding of purified spike protein. Both MUC1 and MUC16 are expressed on the surface of human organoid-derived air-liquid interface (ALI) differentiated airway cultures and StcE treatment led to mucin removal and increased levels of SARS-CoV-2 replication. In these cultures, MUC1 was highly expressed in non-ciliated cells while MUC16 was enriched in goblet cells. In conclusion, the glycosylated extracellular domains of different transmembrane mucins might have similar protective functions in different respiratory cell types by restricting SARS-CoV-2 binding and entry.
Topics: Humans; Mucins; Angiotensin-Converting Enzyme 2; COVID-19; SARS-CoV-2; CA-125 Antigen; Lung; Polysaccharides
PubMed: 37561789
DOI: 10.1371/journal.ppat.1011571 -
Human Vaccines & Immunotherapeutics Dec 2023In immune processes, molecular - molecular interactions are complex. As MUC1 often appears to be an important molecule in inflammation and tumor immunity, it is...
In immune processes, molecular - molecular interactions are complex. As MUC1 often appears to be an important molecule in inflammation and tumor immunity, it is necessary to summarize the leading countries, authors, journals, and the cooperation among these entities and, most importantly, to determine the main research directions related to MUC1 in this field and the associated research frontiers. A total of 3,397 related studies published from 2012-2021 were retrieved from the Web of Science core database. The search strategy is TS= (MUC1 OR Mucin-1) refined by WEB OF SCIENCE CATEGORY (IMMUNOLOGY) AND [excluding] PUBLICATION YEARS: (2022) AND DOCUMENT TYPES: (ARTICLE OR REVIEW) AND LANGUAGES: (ENGLISH) AND WEB OF SCIENCE INDEX: (Web of Science Core Collection. SCI), with a timespan of 2012 to 2021. Documented bibliometric visual analysis was performed by CiteSpace and VOSviewer. The number of studies has increased every year. There are 1,982 articles and 1,415 reviews from 89 countries and regions, 3,722 organizations, 1,042 journals, and 17,948 authors. The United States, China, and Germany are the major countries producing publications on this issue. The most published author is Finn OJ and the most influential author is June CH. The key words "chimeric antigen receptor" and "T-cell" highlight the current hot spots and future trends in this field. Research on MUC1 in the field of immunology is still evolving. Through the bibliometric analysis of the existing publications, the current research hotspots and future development trends in this field can be obtained.
Topics: Mucin-1; Bibliometrics; China; Databases, Factual; Germany
PubMed: 36744407
DOI: 10.1080/21645515.2023.2172278 -
Nature Communications Oct 2023Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and...
Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome.
Topics: Hepatitis A Virus Cellular Receptor 2; Mucins; Polysaccharide-Lyases; Polysaccharides
PubMed: 37794035
DOI: 10.1038/s41467-023-41756-y -
Journal of Ovarian Research Aug 2023MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding...
BACKGROUND
MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on the surface of natural killer cells (NK cells), B cells, and monocytes. However, the role of MUC16 on neutrophils in the tumor microenvironment remains to be further explored.
METHODS
The correlation between the proportion and count of peripheral blood cells, serum inflammatory-related factors and serum MUC16 (CA125) level in patients was constructed based on clinical samples. RNAseq data was obtained from TCGA and sequencing of ovarian cancer tissues, followed by TIMER immune cell infiltration and correlation analysis. Ovarian cancer organoid was constructed to stimulate neutrophils with immunophenotype identification by qPCR and flow cytometry. MUC16 protein stimulation to neutrophils validated the role of MUC16 under the analysis of RNA sequencing and inhibition of NK cytotoxicity in vitro.
RESULTS
The serum MUC16 level was positively correlated with the proportion and count of peripheral blood neutrophils, neutrophil-to-lymphocyte ratio (NLR) and inflammatory factors IL-6, IL-8, IL-10 and IL-2R. Siglec-9, the receptor of MUC16, was expressed on neutrophils and was positively correlated to neutrophil infiltration in ovarian cancer. After the stimulation of ovarian cancer organoids and MUC16 respectively, the proportions of CD11b, CD66b, and ICAM-1 neutrophils were significantly increased, while the proportion of CXCR4 neutrophils was slightly decreased, with increasing of of inflammatory factors MMP9, IL-8, OSM, IL-1β, TNF-α, CXCL3, and ROS. RNA-sequencing analysis revealed that inflammatory response, TNFA signaling pathway, and IL6-related pathway were upregulated in MUC16-stimulated neutrophils, accompanied by high expression of immunosuppression-related factors HHLA2, IL-6, TNFRSF9, ADORA2A, CD274 (PD-L1), and IDO1. NK cytotoxicity was decreased when treated by supernanant of MUC16-stimulated neutrophils in vitro.
CONCLUSION
MUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.
Topics: Female; Humans; Ovarian Neoplasms; Interleukin-6; Interleukin-8; Neutrophils; B-Lymphocytes; CA-125 Antigen; Tumor Microenvironment; Membrane Proteins; Immunoglobulins
PubMed: 37644468
DOI: 10.1186/s13048-023-01207-0