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Machado GC, Ferrer VP. MUC1 and MUC4 expression are inversely correlated and trigger immunological response and transport pathways in adult-type diffuse gliomas. Comput Biol Med 2025; 187:109730. [PMID: 39889447 DOI: 10.1016/j.compbiomed.2025.109730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 01/17/2025] [Accepted: 01/18/2025] [Indexed: 02/03/2025]
Abstract
Adult-type diffuse gliomas arise from glial or progenitor cells. These tumors are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or IDH-mutant oligodendroglioma with co-deletion of chromosomal arms 1p and 19q, both of which could be either slow-growing tumors, or glioblastoma (GBM), which is a more aggressive tumor. Despite advances in diagnosis and treatment, the median survival time after GBM diagnosis remains low at approximately 15 months, with a 5-year overall survival (OS) rate of 6.8 %. Therefore, new biomarker and therapeutic target discoveries are required to improve prognosis. Mucin 1 (MUC1) and MUC4 are membrane-bound mucins and potential biomarkers of several tumors. However, the role of these mucins in adult gliomas has not been well explored. In this retrospective study, in silico analysis of data from patients with adult-type diffuse glioma revealed differential methylation and expression patterns of MUC1 and MUC4 between GBM and non-GBM groups. In the GBM group, decreased methylation and elevated expression of MUC1 were observed (r = -0.25, p < 0.0001), whereas increased methylation and decreased expression of MUC4 were observed (r = -0.13, p = 0.1344). Conversely, in the non-GBM group, MUC1 exhibited higher methylation and lower expression (r = -0.27, p < 0.0001), whereas MUC4 showed lower methylation and higher expression (r = -0.32, p < 0.0001). The expression of these genes influenced OS in adult patients with glioma (p = 0.0344), with high MUC1 and low MUC4 expression associated with worse OS. MUC1 and MUC4 expression correlated with that of MUC20 in both GBM (r = 0.54) and non-GBM (r = 0.53) groups (p < 0.0001). Functional enrichment analysis identified the biological roles of MUC1-co-expressed genes as involvement in innate immunity, antigen processing, and proinflammatory responses in both the non-GBM and GBM groups, and integrin-based signaling pathways in the GBM group. MUC4-co-expressed genes are involved in ion transport in GBM patients. Using molecular docking, we observed that MUC1 domains physically interact with immune response-related proteins, such as receptors for advanced glycation end products (RAGE), major histocompatibility complex II (MHC-II), and extracellular matrix receptor integrin alpha 2 (ITGA2). To our knowledge, this is the first retrospective study and in silico analysis demonstrating the relevance and correlation of MUC1 and MUC4 in adult gliomas. These findings elucidate the molecular mechanisms underlying adult-type diffuse glioma progression and highlight MUC1 and MUC4 as potential prognostic markers and therapeutic targets for glioma management.
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Affiliation(s)
- Gabriel Cardoso Machado
- Graduate Program in Pathological Anatomy, Faculty of Medicine, Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Laboratory of Cell and Molecular Biology of Tumors, Department of Cell and Molecular Biology, Biology Institute, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil
| | - Valéria Pereira Ferrer
- Graduate Program in Pathological Anatomy, Faculty of Medicine, Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Laboratory of Cell and Molecular Biology of Tumors, Department of Cell and Molecular Biology, Biology Institute, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil.
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2
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Fritsche S, Möckl L. A framework for the simulation of individual glycan coordinates to analyze spatial relationships within the glycocalyx. Front Cell Dev Biol 2025; 12:1519831. [PMID: 39839671 PMCID: PMC11747212 DOI: 10.3389/fcell.2024.1519831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 12/13/2024] [Indexed: 01/23/2025] Open
Abstract
The glycocalyx is a dense and dynamic layer of glycosylated species that covers every cell in the human body. It plays crucial roles in various cellular processes in health and disease, such as cancer immune evasion, cancer immune therapy, blastocyst implantation, and functional attenuation of membrane protein diffusion. In addition, alterations in glycocalyx structure may play an important role in ocular surface diseases, e.g., dry eye disease. Despite the emerging importance of the glycocalyx, various aspects of its functional organization remain elusive to date. A central reason for this elusiveness is the nanoscale dimension of the glycocalyx in conjunction with its high structural complexity, which is not accessible to observation with conventional light microscopy. Recent advances in super-resolution microscopy have enabled resolutions down to the single-digit nanometer range. In order to fully leverage the potential of these novel methods, computational frameworks that allow for contextualization of the resulting experimental data are required. Here, we present a simulation-based approach to analyze spatial relationships of glycan components on the cell membrane based on known geometrical parameters. We focus on sialic acids in this work, but the technique can be adapted to any glycan component of interest. By integrating data from mass spectrometry and quantitative biological studies, these simulations aim to model possible experimental outcomes, which can then be used for further analysis, such as spatial point statistics. Importantly, we include various experimental considerations, such as labeling and detection efficiency. This approach may contribute to establishing a new standard of connection between geometrical and molecular-resolution data in service of advancing our understanding of the functional role of the glycocalyx in biology as well as its clinical potential.
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Affiliation(s)
- Sarah Fritsche
- Department of Physics, Faculty of Sciences, FAU Erlangen-Nuremberg, Erlangen, Germany
- Max Plank Institute for the Science of Light, Erlangen, Germany
| | - Leonhard Möckl
- Department of Physics, Faculty of Sciences, FAU Erlangen-Nuremberg, Erlangen, Germany
- Max Plank Institute for the Science of Light, Erlangen, Germany
- Department of Medicine/CITABLE, FAU Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
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3
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Hrudka J, Kalinová M, Fišerová H, Jelínková K, Nikov A, Waldauf P, Matěj R. Molecular genetic analysis of colorectal carcinoma with an aggressive extraintestinal immunohistochemical phenotype. Sci Rep 2024; 14:22241. [PMID: 39333321 PMCID: PMC11437151 DOI: 10.1038/s41598-024-72687-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 09/10/2024] [Indexed: 09/29/2024] Open
Abstract
Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers' prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct "non-intestinal" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS. CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.
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Affiliation(s)
- Jan Hrudka
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 1150/50, Praha 10, 10034, Prague, Czech Republic.
| | - Markéta Kalinová
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 1150/50, Praha 10, 10034, Prague, Czech Republic
- Central Laboratories, University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Hana Fišerová
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 1150/50, Praha 10, 10034, Prague, Czech Republic
| | - Karolína Jelínková
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 1150/50, Praha 10, 10034, Prague, Czech Republic
| | - Andrej Nikov
- Department of General Surgery, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Petr Waldauf
- Department of Anaesthesia and Intensive Care Medicine, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Radoslav Matěj
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 1150/50, Praha 10, 10034, Prague, Czech Republic
- Department of Pathology, 1st Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic
- Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic
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Pérez-Polo S, Mena AR, Barros L, Borrajo P, Pazos M, Carrera M, Gestal C. Decoding Octopus Skin Mucus: Impact of Aquarium-Maintenance and Senescence on the Proteome Profile of the Common Octopus ( Octopus vulgaris). Int J Mol Sci 2024; 25:9953. [PMID: 39337441 PMCID: PMC11431876 DOI: 10.3390/ijms25189953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 09/04/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
The common octopus (Octopus vulgaris) is an excellent candidate for aquaculture diversification, due to its biological traits and high market demand. To ensure a high-quality product while maintaining welfare in captive environments, it is crucial to develop non-invasive methods for testing health biomarkers. Proteins found in skin mucus offer a non-invasive approach to monitoring octopus welfare. This study compares the protein profiles in the skin mucus of wild, aquarium-maintained, and senescent specimens to identify welfare biomarkers. A tandem mass tag (TMT) coupled with an Orbitrap Eclipse Tribrid mass spectrometer was used to create a reference dataset from octopus skin mucus, identifying 1496 non-redundant protein groups. Although similar profiles were observed, differences in relative abundances led to the identification of potential biomarkers, including caspase-3-like, protocadherin 4, deleted in malignant brain tumors, thioredoxin, papilin, annexin, cofilin and mucin-4 proteins. Some of these proteins also revealed potential as bioactive peptides. This investigation provides the most extensive analysis of the skin mucus proteome in the common octopus and is the first to explore how aquarium maintenance and senescence alter the mucus proteome. This research highlights the potential of skin mucus protein/peptides as non-invasive monitoring biomarkers in cultured animals.
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Affiliation(s)
| | | | | | | | | | - Mónica Carrera
- Instituto de Investigaciones Marinas (IIM-CSIC), Spanish National Research Council (CSIC), Eduardo Cabello 6, 36208 Vigo, Spain; (S.P.-P.); (A.R.M.); (L.B.); (P.B.); (M.P.)
| | - Camino Gestal
- Instituto de Investigaciones Marinas (IIM-CSIC), Spanish National Research Council (CSIC), Eduardo Cabello 6, 36208 Vigo, Spain; (S.P.-P.); (A.R.M.); (L.B.); (P.B.); (M.P.)
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Rashid S, Singh N, Rashid S, Das P, Gupta S, Chauhan SS, Sati HC, Dash NR, Sharma A, Dey S, Saraya A. Clinical Significance of MUC4 and Associated Proteins in Pancreatic and Periampullary Cancers. Pancreas 2024; 53:e595-e602. [PMID: 38696350 DOI: 10.1097/mpa.0000000000002340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/04/2024]
Abstract
OBJECTIVE This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. MATERIALS AND METHODS Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. RESULT MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. CONCLUSIONS Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.
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MESH Headings
- Humans
- Mucin-4/metabolism
- Mucin-4/genetics
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/blood
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/pathology
- Male
- Middle Aged
- Female
- Aged
- Cholangiocarcinoma/genetics
- Cholangiocarcinoma/metabolism
- Cholangiocarcinoma/diagnosis
- Immunohistochemistry
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Biomarkers, Tumor/blood
- Adult
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/diagnosis
- Pancreatitis, Chronic/blood
- Case-Control Studies
- Ampulla of Vater/metabolism
- Ampulla of Vater/pathology
- Gene Expression Regulation, Neoplastic
- Common Bile Duct Neoplasms/metabolism
- Common Bile Duct Neoplasms/genetics
- Common Bile Duct Neoplasms/diagnosis
- Common Bile Duct Neoplasms/pathology
- Clinical Relevance
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Affiliation(s)
| | - Nidhi Singh
- From the Department of Gastroenterology and HNU
| | | | | | | | | | | | | | - Atul Sharma
- Medical Oncology, Institute Rotary Cancer Hospital
| | - Sharmistha Dey
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
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6
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Tang YH, Leng JX, Yang G, Gao XD, Liu YS, Fujita M. Production of CA125 with Tn antigens using a glycosylphosphatidylinositol anchoring system. J Biochem 2024; 176:23-34. [PMID: 38382634 DOI: 10.1093/jb/mvae019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/23/2024] Open
Abstract
Cancer antigen 125 (CA125) is a serum marker associated with ovarian cancer. Despite its widespread use, CA125 levels can also be elevated in benign conditions. Recent reports suggest that detecting serum CA125 that carries the Tn antigen, a truncated O-glycan containing only N-acetylgalactosamine on serine or threonine residues, can improve the specificity of ovarian cancer diagnosis. In this study, we engineered cells to express CA125 with a Tn antigen. To achieve this, we knocked out C1GALT1 and SLC35A1, genes encoding Core1 synthase and a transporter for cytidine-5'-monophospho-sialic acid respectively, in human embryonic kidney 293 (HEK293) cells. In ClGALT1-SLC35A1-knockout (KO) cells, the expression of the Tn antigen showed a significant increase, whereas the expression of the T antigen (galactose-β1,3-N-acetylgalactosamine on serine or threonine residues) was decreased. Due to the inefficient secretion of soluble CA125, we employed a glycosylphosphatidylinositol (GPI) anchoring system. This allowed for the expression of GPI-anchored CA125 on the cell surface of ClGALT1-SLC35A1-KO cells. Cells expressing high levels of GPI-anchored CA125 were then enriched through cell sorting. By knocking out the PGAP2 gene, the GPI-anchored form of CA125 was converted to a secretory form. Through the engineering of O-glycans and the use of a GPI-anchoring system, we successfully produced CA125 with Tn antigen modification.
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Affiliation(s)
- Yu-He Tang
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Ji-Xiong Leng
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Ganglong Yang
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Xiao-Dong Gao
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Yi-Shi Liu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, China
| | - Morihisa Fujita
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, China
- Institute for Glyco-core Research (iGCORE), Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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Aguilar Díaz de león JS, Thirumurty M, Ly N. Surface plasmon resonance microscopy identifies glycan heterogeneity in pancreatic cancer cells that influences mucin-4 binding interactions. PLoS One 2024; 19:e0304154. [PMID: 38776309 PMCID: PMC11111020 DOI: 10.1371/journal.pone.0304154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/07/2024] [Indexed: 05/24/2024] Open
Abstract
Membrane proteins are the main targets of therapeutic drugs and most of them are glycosylated. Glycans play pivotal roles in several biological processes, and glycosylation changes are a well-established hallmark of several types of cancer, including pancreatic cancer, that contribute to tumor growth. Mucin-4 (MUC-4) is a membrane glycoprotein which is associated with pancreatic cancer and metastasis, and it has been targeted as a promising vaccine candidate. In this study, Surface Plasmon Resonance Microscopy (SPRM) was implemented to study complex influences of the native N-glycan cellular environment on binding interactions to the MUC-4 receptor as this is currently the only commercially available label-free technique with high enough sensitivity and resolution to measure binding kinetics and heterogeneity on single cells. Such unique capability enables for a more accurate understanding of the "true" binding interactions on human cancer cells without disrupting the native environment of the target MUC-4 receptor. Removal of N-linked glycans in pancreatic cancer cells using PNGase F exposed heterogeneity in Concanavalin (Con A) binding by revealing three new binding populations with higher affinities than the glycosylated control cells. Anti-MUC-4 binding interactions of enzymatically N-linked deglycosylated pancreatic cancer cells produced a 25x faster association and 37x higher affinity relative to the glycosylated control cells. Lastly, four interaction modes were observed for Helix Pomatia Agglutinin (HPA) binding to the glycosylated control cells, but shifted and increased in activity upon removal of N-linked glycans. These results identified predominant interaction modes of glycan and MUC-4 in pancreatic cancer cells, the kinetics of their binding interactions were quantified, and the influence of N-linked glycans in MUC-4 binding interactions was revealed.
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Affiliation(s)
| | - Miyuki Thirumurty
- Biosensing Instrument Inc., Tempe, Arizona, United States of America
| | - Nguyen Ly
- Biosensing Instrument Inc., Tempe, Arizona, United States of America
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Riera-Ferrer E, Del Pozo R, Muñoz-Berruezo U, Palenzuela O, Sitjà-Bobadilla A, Estensoro I, Piazzon MC. Mucosal affairs: glycosylation and expression changes of gill goblet cells and mucins in a fish-polyopisthocotylidan interaction. Front Vet Sci 2024; 11:1347707. [PMID: 38655531 PMCID: PMC11035888 DOI: 10.3389/fvets.2024.1347707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Introduction Secreted mucins are highly O-glycosylated glycoproteins produced by goblet cells in mucosal epithelia. They constitute the protective viscous gel layer overlying the epithelia and are involved in pathogen recognition, adhesion and expulsion. The gill polyopisthocotylidan ectoparasite Sparicotyle chrysophrii, feeds on gilthead seabream (Sparus aurata) blood eliciting severe anemia. Methods Control unexposed and recipient (R) gill samples of gilthead seabream experimentally infected with S. chrysophrii were obtained at six consecutive times (0, 11, 20, 32, 41, and 61 days post-exposure (dpe)). In histological samples, goblet cell numbers and their intensity of lectin labelling was registered. Expression of nine mucin genes (muc2, muc2a, muc2b, muc5a/c, muc4, muc13, muc18, muc19, imuc) and three regulatory factors involved in goblet cell differentiation (hes1, elf3, agr2) was studied by qPCR. In addition, differential expression of glycosyltransferases and glycosidases was analyzed in silico from previously obtained RNAseq datasets of S. chrysophrii-infected gilthead seabream gills with two different infection intensities. Results and Discussion Increased goblet cell differentiation (up-regulated elf3 and agr2) leading to neutral goblet cell hyperplasia on gill lamellae of R fish gills was found from 32 dpe on, when adult parasite stages were first detected. At this time point, acute increased expression of both secreted (muc2a, muc2b, muc5a/c) and membrane-bound mucins (imuc, muc4, muc18) occurred in R gills. Mucins did not acidify during the course of infection, but their glycosylation pattern varied towards more complex glycoconjugates with sialylated, fucosylated and branched structures, according to lectin labelling and the shift of glycosyltransferase expression patterns. Gilthead seabream gill mucosal response against S. chrysophrii involved neutral mucus hypersecretion, which could contribute to worm expulsion and facilitate gas exchange to counterbalance parasite-induced hypoxia. Stress induced by the sparicotylosis condition seems to lead to changes in glycosylation characteristic of more structurally complex mucins.
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Affiliation(s)
| | | | | | | | | | - Itziar Estensoro
- Fish Pathology Group, Instituto de Acuicultura Torre de la Sal, Consejo Superior de Investigaciones Científicas (IATS, CSIC), Castellón, Spain
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9
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Stricher M, Vigneron P, Delbecq F, Sarde CO, Egles C. The microalga Volvox carteri as a cell supportive building block for tissue engineering. Mater Today Bio 2024; 25:101013. [PMID: 38464496 PMCID: PMC10923841 DOI: 10.1016/j.mtbio.2024.101013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/18/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024] Open
Abstract
Background V. carteri f. nagariensis constitutes, in its most simplified form, a cellularized spheroid built around and stabilised by a form of primitive extracellular matrix (ECM). Methods We developed a modular approach to soft tissue engineering, by compact stacking V. carteri-based building blocks. This approach is made possible by the structure and cell adhesive properties of these building blocks, which results from the composition of their algal ECM. Results A primary biocompatibility assessment demonstrated the cytocompatibility of the algal suspension, its histogenesis-promoting properties, and that it did not induce an inflammatory response in vitro. These results allowed us to consider the use of this algal suspension for soft tissue augmentation, and to initiate an in vivo biocompatibility study. V. carteri exhibited cellular fate-directing properties, causing (i) fibroblasts to take on an alkaline phosphatase+ stem-cell-like phenotype and (ii) both human adipose-derived stem cells and mouse embryonic stem cells to differentiate into preadipocytes to adipocytes. The ability of V. carteri to support histogenesis and adipogenesis was also observed in vivo by subcutaneous tissue augmentation of athymic mice, highlighting the potential of V. carteri to support or influence tissue regeneration. Conclusions We present for the first time V. carteri as an innovative and inspiring biomaterial for tissue engineering and soft tissue regeneration. Its strategies in terms of shape, structure and composition can be central in the design of a new generation of bio-inspired heterogeneous biomaterials recapitulating more appropriately the complexity of body tissues when guiding their regeneration.
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Affiliation(s)
- Mathilde Stricher
- Université de Technologie de Compiègne, CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu, CEDEX CS 60 319, 60 203, Compiègne, France
| | - Pascale Vigneron
- Université de Technologie de Compiègne, CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu, CEDEX CS 60 319, 60 203, Compiègne, France
| | - Frederic Delbecq
- Université de Technologie de Compiègne, ESCOM, TIMR (Integrated Transformations of Renewable Matter), Centre de Recherche Royallieu, CEDEX CS 60 319, 60 203, Compiègne, France
| | - Claude-Olivier Sarde
- Université de Technologie de Compiègne, ESCOM, TIMR (Integrated Transformations of Renewable Matter), Centre de Recherche Royallieu, CEDEX CS 60 319, 60 203, Compiègne, France
| | - Christophe Egles
- Université de Technologie de Compiègne, CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu, CEDEX CS 60 319, 60 203, Compiègne, France
- Univ Rouen Normandie, INSA Rouen Normandie, CNRS, Normandie Univ, PBS UMR 6270, 55 Rue Saint-Germain, 27 000, Évreux, France
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10
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Yeshaya N, Gupta PK, Dym O, Morgenstern D, Major DT, Fass D. VWD domain stabilization by autocatalytic Asp-Pro cleavage. Protein Sci 2024; 33:e4929. [PMID: 38380729 PMCID: PMC10880436 DOI: 10.1002/pro.4929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/17/2024] [Accepted: 01/30/2024] [Indexed: 02/22/2024]
Abstract
Domains known as von Willebrand factor type D (VWD) are found in extracellular and cell-surface proteins including von Willebrand factor, mucins, and various signaling molecules and receptors. Many VWD domains have a glycine-aspartate-proline-histidine (GDPH) amino-acid sequence motif, which is hydrolytically cleaved post-translationally between the aspartate (Asp) and proline (Pro). The Fc IgG binding protein (FCGBP), found in intestinal mucus secretions and other extracellular environments, contains 13 VWD domains, 11 of which have a GDPH cleavage site. In this study, we investigated the structural and biophysical consequences of Asp-Pro peptide cleavage in a representative FCGBP VWD domain. We found that endogenous Asp-Pro cleavage increases the resistance of the domain to exogenous proteolytic degradation. Tertiary structural interactions made by the newly generated chain termini, as revealed by a crystal structure of an FCGBP segment containing the VWD domain, may explain this observation. Notably, the Gly-Asp peptide bond, upstream of the cleavage site, assumed the cis configuration in the structure. In addition to these local features of the cleavage site, a global organizational difference was seen when comparing the FCGBP segment structure with the numerous other structures containing the same set of domains. Together, these data illuminate the outcome of GDPH cleavage and demonstrate the plasticity of proteins with VWD domains, which may contribute to their evolution for function in a dynamic extracellular environment.
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Affiliation(s)
- Noa Yeshaya
- Department of Chemical and Structural BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Prashant Kumar Gupta
- Department of Chemistry and Institute for Nanotechnology & Advanced MaterialsBar‐Ilan UniversityRamat‐GanIsrael
| | - Orly Dym
- Department of Life Sciences Core FacilitiesWeizmann Institute of ScienceRehovotIsrael
| | - David Morgenstern
- De Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized MedicineWeizmann Institute of ScienceRehovotIsrael
| | - Dan Thomas Major
- Department of Chemistry and Institute for Nanotechnology & Advanced MaterialsBar‐Ilan UniversityRamat‐GanIsrael
| | - Deborah Fass
- Department of Chemical and Structural BiologyWeizmann Institute of ScienceRehovotIsrael
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11
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Liu C, Shen X, Yan L, Qu R, Wang Y, He Y, Zhan Z, Chen P, Lin F. Controllable self-assembled DNA nanomachine enable homogeneous rapid electrochemical one-pot assay of lung cancer circulating tumor cells. Biosens Bioelectron 2024; 246:115865. [PMID: 38035517 DOI: 10.1016/j.bios.2023.115865] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 11/17/2023] [Accepted: 11/18/2023] [Indexed: 12/02/2023]
Abstract
A homogeneous rapid (45 min) one-pot electrochemical (EC) aptasensor was established to quantitatively detect circulating tumor cells (CTCs) in lung cancer patients using mucin 1 as a marker. The core of this study is that the three single-stranded DNA (Y1, Y2, and Y3) could be hybridized to form Y-shaped DNA (Y-DNA) and further self-assemble to form DNA nanosphere. The aptamer of mucin 1 could be complementary and paired with Y1, thus disrupting the conformation of the DNA nanosphere. When mucin 1 was present, the aptamer combined specifically with mucin 1, thus preserving the DNA nanosphere structure. Methylene blue (MB) acted as a signal reporter, which could be embedded between two base pairs in the DNA nanosphere to form a DNA nanosphere-MB complex, reducing free MB and resulting in a lower electrochemical signal. The results demonstrated that the linear ranges for mucin 1 and A549 cells were 1 ag/mL-1 fg/mL and 1-100 cells/mL, respectively, with minimum detectable concentrations were 1 ag/mL and 1 cell/mL, respectively. The quantitative analysis of CTCs in 44 clinical blood samples was performed, and the results were consistent with the computerized tomography (CT) images, pathological findings and folate receptor-polymerase chain reaction (FR-PCR) kits. The receiver operating characteristic (ROC) curve exhibited an area under the curve (AUC) value of 0.970. The assay revealed 100% specificity and 94.1% sensitivity. It is believed that this electrochemical aptasensor could provide a new approach to detect CTCs.
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Affiliation(s)
- Chengxin Liu
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xu Shen
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Li Yan
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Runlian Qu
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yue Wang
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yaqin He
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zixuan Zhan
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Piaopiao Chen
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - Feng Lin
- Department of Thoracic Surgery, Department of Laboratory Medicine, Med+X Center for Manufacturing, Out-patient Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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12
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Leoncini G, Cari L, Ronchetti S, Donato F, Caruso L, Calafà C, Villanacci V. Mucin Expression Profiles in Ulcerative Colitis: New Insights on the Histological Mucosal Healing. Int J Mol Sci 2024; 25:1858. [PMID: 38339134 PMCID: PMC10855303 DOI: 10.3390/ijms25031858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
A structural weakness of the mucus barrier (MB) is thought to be a cause of ulcerative colitis (UC). This study aims to investigate the mucin (MUC) composition of MB in normal mucosa and UC. Ileocolonic biopsies were taken at disease onset and after treatment in 40 patients, including 20 with relapsing and 20 with remitting UC. Ileocolonic biopsies from 10 non-IBD patients were included as controls. Gut-specific MUC1, MUC2, MUC4, MUC5B, MUC12, MUC13, MUC15, and MUC17 were evaluated immunohistochemically. The promoters of mucin genes were also examined. Normal mucosa showed MUC2, MUC5B, and MUC13 in terminal ileum and colon, MUC17 in ileum, and MUC1, MUC4, MUC12, and MUC15 in colon. Membranous, cytoplasmic and vacuolar expressions were highlighted. Overall, the mucin expression was abnormal in UC. Derangements in MUC1, MUC4, and MUC5B were detected both at onset and after treatment. MUC2 and MUC13 were unaffected. Sequence analysis revealed glucocorticoid-responsive elements in the MUC1 promoter, retinoic-acid-responsive elements in the MUC4 promoter, and butyrate-responsive elements in the MUC5B promoter. In conclusion, MUCs exhibited distinct expression patterns in the gut. Their expression was disrupted in UC, regardless of the treatment protocols. Abnormal MUC1, MUC4, and MUC5B expression marked the barrier dysfunction in UC.
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Affiliation(s)
- Giuseppe Leoncini
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy;
| | - Luigi Cari
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Simona Ronchetti
- Pharmacology Division, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Francesco Donato
- Unit of Hygiene, Epidemiology and Public Health, University of Brescia, 25123 Brescia, Italy
| | - Laura Caruso
- Pathology Unit, Department of Pathology and Laboratory Medicine, Desenzano del Garda Hospital, ASST del Garda, 25015 Brescia, Italy
| | - Cristina Calafà
- Pathology Unit, Department of Pathology and Laboratory Medicine, Desenzano del Garda Hospital, ASST del Garda, 25015 Brescia, Italy
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13
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Chaudhuri AG, Samanta S, Dey M, Raviraja NS, Dey S. Role of Alpha-Fetoprotein in the Pathogenesis of Cancer. J Environ Pathol Toxicol Oncol 2024; 43:57-76. [PMID: 38505913 DOI: 10.1615/jenvironpatholtoxicoloncol.2023049145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024] Open
Abstract
Alpha-fetoprotein (AFP) belongs to the albuminoid protein family and is considered as the fetal analog of serum albumin. This plasma protein is initially synthesized in the fetal liver and yolk sac and shows a maximum peak near the end of the first trimester. Later, concentrations begin to decline prenatally and drop precipitously after birth. This protein has three key ligand-binding pockets for interactions with various biomolecules. It contains multiple phosphorylation and acetylation sites for the regulation of physiological and pathophysiological states. High serum AFP titer is an established biomarker for yolk sac, embryonal and hepatocellular carcinoma. The present review critically analyzes the chemical nature, receptors, clinical implications, and therapeutic aspects of AFP, underpinning the development of different types of cancer.
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Affiliation(s)
- Alok Ghosh Chaudhuri
- Department of Physiology, Vidyasagar College, Kolkata 700 006, West Bengal, India
| | - Saptadip Samanta
- Department of Physiology, Midnapore College, Midnapore, Paschim Medinipur 721101, West Bengal, India
| | - Monalisha Dey
- Department of Physiology, Vidyasagar College, Kolkata 700 006, West Bengal, India
| | - N S Raviraja
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal 576 104, Karnataka, India
| | - Souvik Dey
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal 576 104, Karnataka, India
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14
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Hu C, Huang C, Hsu M, Chien H, Wu P, Chen Y, Jeng Y, Tang S, Chung M, Shen C, Chang M, Chang Y, Tien Y, Lee W. Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301240. [PMID: 37964407 PMCID: PMC10754145 DOI: 10.1002/advs.202301240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 08/22/2023] [Indexed: 11/16/2023]
Abstract
Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
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Affiliation(s)
- Chun‐Mei Hu
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
| | - Chien‐Chang Huang
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
- Biomedical Translation Research CenterAcademia SinicaTaipei11529Taiwan
| | - Min‐Fen Hsu
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
| | - Hung‐Jen Chien
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
| | - Pei‐Jung Wu
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
| | - Yi‐Ing Chen
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
| | - Yung‐Ming Jeng
- Department of PathologyNational Taiwan University HospitalTaipei10041Taiwan
- Graduate Institute of Pathology, College of MedicineNational Taiwan UniversityTaipei10041Taiwan
| | - Shiue‐Cheng Tang
- Department of Medical ScienceNational Tsing Hua UniversityHsinchu30013Taiwan
| | - Mei‐Hsin Chung
- Department of PathologyNational Taiwan University Hospital−Hsinchu BranchHsinchu30331Taiwan
| | - Chia‐Ning Shen
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
- Biomedical Translation Research CenterAcademia SinicaTaipei11529Taiwan
| | - Ming‐Chu Chang
- Department of Internal MedicineNational Taiwan University HospitalTaipei10041Taiwan
| | - Yu‐Ting Chang
- Department of Internal MedicineNational Taiwan University HospitalTaipei10041Taiwan
| | - Yu‐Wen Tien
- Department of SurgeryNational Taiwan University HospitalTaipei10041Taiwan
| | - Wen‐Hwa Lee
- Genomics Research CenterAcademia SinicaTaipei11529Taiwan
- Drug Development CenterChina Medical UniversityTaichung40402Taiwan
- Department of Biological ChemistryUniversity of CaliforniaIrvineCA92697USA
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15
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Khan N, Rehman B, Almanaa TN, Aljahdali SM, Waheed Y, Ullah A, Asfandayar M, Al-Harbi AI, Naz T, Arshad M, Sanami S, Ahmad S. A novel therapeutic approach to prevent Helicobacter pylori induced gastric cancer using networking biology, molecular docking, and simulation approaches. J Biomol Struct Dyn 2023; 42:13876-13889. [PMID: 37962871 DOI: 10.1080/07391102.2023.2279276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 10/27/2023] [Indexed: 11/15/2023]
Abstract
Helicobacter pylori infects 50% of the world population and in 80% of cases, the infection progresses to the point where an ulcer develops leading to gastric cancer (GC). This study aimed to prevent GC by predicting Hub genes that are inducing GC. Furthermore, the study objective was to screen inhibitory molecules that block the function of predicted genes through several biophysical approaches. These proteins, such as Mucin 4 (MUC4) and Baculoviral IAP repeat containing 3 (BIRC3), had LogFC values of 2.28 and 3.39, respectively, and were found to be substantially expressed in those who had H. pylori infection. The MUC4 and BIRC3 inhibit apoptosis of infected cells and promote cancerous cell survival. The proteins were examined for their Physico-chemical characteristics, 3D structure and secondary structure analysis, solvent assessable surface area (SASA), active site identification, and network analysis. The MUC4 and BIRC3 expression was inhibited by docking eighty different compounds collected from the ZINC database. Fifty-seven compounds were successfully docked into the active site resulting in the lowest binding energy scores. The ZINC585267910 and ZINC585268691 compounds showed the lowest binding energy of -8.5 kcal/mol for MUC4 and -7.1 kcal/mol for BIRC3, respectively, and were considered best-docked solutions for molecular dynamics simulations. The mean root mean square deviation (RMSD) value for the ZINC585267910-MUC4 complex was 0.86 Å and the ZINC585268691-BIRC3 complex was 1.01 Å. The net MM/GBSA energy value of the ZINC585267910-MUC4 complex estimated was -46.84 kcal/mol and that of the ZINC585268691-BIRC3 complex was -44.84 kcal/mol. In a nutshell, the compounds might be investigated further as an inhibitor of the said proteins to stop the progress of GC induced by H. pylori.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Nadeem Khan
- Department of Health and Biological Sciences, Abasyn University, Peshawar, Pakistan
| | - Bushra Rehman
- Institute of Biotechnology and Microbiology, Bacha Khan University, Charsadaa, Pakistan
| | - Taghreed N Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | | | - Yasir Waheed
- Office of Research, Innovation and Commercialization, Shaheed Zulfiqar Ali Bhutto Medical University (SZABMU), Islamabad, Pakistan
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - Asad Ullah
- Department of Health and Biological Sciences, Abasyn University, Peshawar, Pakistan
| | - Muhammad Asfandayar
- Department of Health and Biological Sciences, Abasyn University, Peshawar, Pakistan
| | - Alhanouf I Al-Harbi
- Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia
| | - Tahira Naz
- Department of Chemical and Life Sciences, Qurtuba University of Science and Technology, Peshawar, Pakistan
| | - Muhammad Arshad
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan
| | - Samira Sanami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, Pakistan
- Department of Computer Science, Virginia Tech, Blacksburg, VA, USA
- Department of Natural Sciences, Lebanese American University, Beirut, Lebanon
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16
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Alors-Pérez E, Pedraza-Arevalo S, Blázquez-Encinas R, Moreno-Montilla MT, García-Vioque V, Berbel I, Luque RM, Sainz B, Ibáñez-Costa A, Castaño JP. Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential. J Exp Clin Cancer Res 2023; 42:282. [PMID: 37880792 PMCID: PMC10601233 DOI: 10.1186/s13046-023-02858-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 10/09/2023] [Indexed: 10/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, mainly due to its late diagnosis and lack of effective therapies, translating into a low 5-year 12% survival rate, despite extensive clinical efforts to improve outcomes. International cooperative studies have provided informative multiomic landscapes of PDAC, but translation of these discoveries into clinical advances are lagging. Likewise, early diagnosis biomarkers and new therapeutic tools are sorely needed to tackle this cancer. The study of poorly explored molecular processes, such as splicing, can provide new tools in this regard. Alternative splicing of pre-RNA allows the generation of multiple RNA variants from a single gene and thereby contributes to fundamental biological processes by finely tuning gene expression. However, alterations in alternative splicing are linked to many diseases, and particularly to cancer, where it can contribute to tumor initiation, progression, metastasis and drug resistance. Splicing defects are increasingly being associated with PDAC, including both mutations or dysregulation of components of the splicing machinery and associated factors, and altered expression of specific relevant gene variants. Such disruptions can be a key element enhancing pancreatic tumor progression or metastasis, while they can also provide suitable tools to identify potential candidate biomarkers and discover new actionable targets. In this review, we aimed to summarize the current information about dysregulation of splicing-related elements and aberrant splicing isoforms in PDAC, and to describe their relationship with the development, progression and/or aggressiveness of this dismal cancer, as well as their potential as therapeutic tools and targets.
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Affiliation(s)
- Emilia Alors-Pérez
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Reina Sofía University Hospital (HURS), Cordoba, Spain
| | - Sergio Pedraza-Arevalo
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Reina Sofía University Hospital (HURS), Cordoba, Spain
| | - Ricardo Blázquez-Encinas
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Reina Sofía University Hospital (HURS), Cordoba, Spain
| | - María Trinidad Moreno-Montilla
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Reina Sofía University Hospital (HURS), Cordoba, Spain
| | - Víctor García-Vioque
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Reina Sofía University Hospital (HURS), Cordoba, Spain
| | - Inmaculada Berbel
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Reina Sofía University Hospital (HURS), Cordoba, Spain
| | - Raúl M Luque
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Reina Sofía University Hospital (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERObn), Córdoba, Spain
| | - Bruno Sainz
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Area 3, Cancer, Madrid, Spain
- Gastrointestinal Tumours Research Programme, Biomedical Research Network in Cancer (CIBERONC), Madrid, Spain
| | - Alejandro Ibáñez-Costa
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.
- Reina Sofía University Hospital (HURS), Cordoba, Spain.
| | - Justo P Castaño
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Cordoba, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.
- Reina Sofía University Hospital (HURS), Cordoba, Spain.
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERObn), Córdoba, Spain.
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17
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Arruda BL, Kanefsky RA, Hau S, Janzen GM, Anderson TK, Vincent Baker AL. Mucin 4 is a cellular biomarker of necrotizing bronchiolitis in influenza A virus infection. Microbes Infect 2023; 25:105169. [PMID: 37295769 DOI: 10.1016/j.micinf.2023.105169] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
Influenza A virus (IAV) in the human and swine host infects epithelial cells lining the respiratory tract causing a necrotizing bronchitis and bronchiolitis. These epithelial surfaces are protected by large glycoproteins called mucins. Mucin 4 (MUC4) is a transmembrane mucin that consists of an alpha subunit responsible for surface protection and intracellular beta subunit involved in signal transduction which repress apoptosis and stimulate epithelial proliferation. This study was designed to determine the expression and potential role of MUC4 during IAV infection. We used immunohistochemistry in combination with machine learning image analysis to quantify differential protein expression of MUC4 subunits in IAV-infected and uninfected lung in a porcine model. MUC4 protein basal expression in control animals varied significantly by litter. MUC4 protein expression was significantly increased in bronchioles with necrotizing bronchiolitis compared to histologically normal bronchioles, likely representing a regenerative response to restore mucosal integrity of conducting airways. Understanding the impact of differential MUC4 expression among healthy individuals and during IAV infection will facilitate control strategies by elucidating mechanisms associated with susceptibility to IAV that can be therapeutically or genetically regulated and may be extended to other respiratory diseases.
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Affiliation(s)
- Bailey L Arruda
- Virus and Prion Research Unit, National Animal Disease Center, USDA Agricultural Research Service, 1920 Dayton Ave, Ames, IA 50010, USA.
| | - Rachel A Kanefsky
- Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Rd, North Grafton, MA 01536, USA
| | - Samantha Hau
- Virus and Prion Research Unit, National Animal Disease Center, USDA Agricultural Research Service, 1920 Dayton Ave, Ames, IA 50010, USA
| | - Garrett M Janzen
- Virus and Prion Research Unit, National Animal Disease Center, USDA Agricultural Research Service, 1920 Dayton Ave, Ames, IA 50010, USA
| | - Tavis K Anderson
- Virus and Prion Research Unit, National Animal Disease Center, USDA Agricultural Research Service, 1920 Dayton Ave, Ames, IA 50010, USA
| | - Amy L Vincent Baker
- Virus and Prion Research Unit, National Animal Disease Center, USDA Agricultural Research Service, 1920 Dayton Ave, Ames, IA 50010, USA
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18
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Cloutier JM, Moreland A, Wang L, Kunder CA, Allard G, Wang A, Krings G, Charville GW, Bean GR. Low-grade fibromyxoid sarcoma of the breast: genetic characterization and immunohistochemical comparison to morphologic mimics. Hum Pathol 2023; 139:17-26. [PMID: 37392946 DOI: 10.1016/j.humpath.2023.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/25/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023]
Abstract
Spindle cell lesions of the breast elicit a specific, relatively limited differential diagnosis, and accurate classification often requires careful morphologic evaluation and immunohistochemical workup. Low-grade fibromyxoid sarcoma (LGFMS) is a rare malignant fibroblastic tumor with deceptively bland spindle cell morphology. Involvement of the breast is exceedingly rare. We examined the clinicopathologic and molecular characteristics of three cases of breast/axillary LGFMS. In addition, we interrogated the immunohistochemical expression of MUC4, a commonly used marker of LGFMS, in other breast spindle cell lesions. LGFMS presented in women at 23, 33, and 59 years of age. Tumor size ranged from 0.9 to 4.7 cm. Microscopically, they were circumscribed nodular masses composed of bland spindle cells with fibromyxoid stroma. Immunohistochemically, tumors were diffusely positive for MUC4 and negative for keratin, CD34, S100 protein, and nuclear beta-catenin. Fluorescence in-situ hybridization demonstrated FUS (n = 2) or EWSR1 (n = 1) rearrangements. Next-generation sequencing identified FUS::CREB3L2 and EWSR1::CREB3L1 fusions. MUC4 immunohistochemistry performed on 162 additional breast lesions demonstrated only weak and limited expression in a subset of cases of fibromatosis (10/20, ≤30% staining), scar (5/9, ≤10%), metaplastic carcinoma (4/23, ≤5%), and phyllodes tumor (3/74, ≤10%). MUC4 was entirely negative in cases of pseudoangiomatous stromal hyperplasia (n = 9), myofibroblastoma (n = 6), periductal stromal tumor (n = 3), and cellular/juvenile fibroadenoma (n = 21). LGFMS can rarely occur in the breast and should be considered in the differential diagnosis of breast spindle cell lesions. Strong and diffuse MUC4 expression is highly specific in this histologic context. Detection of an FUS or EWSR1 rearrangement can confirm the diagnosis.
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Affiliation(s)
- Jeffrey M Cloutier
- Department of Pathology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
| | | | - Lin Wang
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Christian A Kunder
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Grace Allard
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Aihui Wang
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Gregor Krings
- Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA 94143, USA
| | - Gregory W Charville
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Gregory R Bean
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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19
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Martinez-Carrasco R, Rachagani S, Batra SK, Argüeso P, Fini ME. Roles unveiled for membrane-associated mucins at the ocular surface using a Muc4 knockout mouse model. Sci Rep 2023; 13:13558. [PMID: 37604830 PMCID: PMC10442421 DOI: 10.1038/s41598-023-40491-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023] Open
Abstract
Membrane-associated mucins (MAMs) are proposed to play critical roles at the ocular surface; however, in vivo evidence has been lacking. Here we investigate these roles by phenotyping of a Muc4 KO mouse. Histochemical analysis for expression of the beta-galactosidase transgene replacing Muc4 revealed a spiraling ribbon pattern across the corneal epithelium, consistent with centripetal cell migration from the limbus. Depletion of Muc4 compromised transcellular barrier function, as evidenced by an increase in rose bengal staining. In addition, the corneal surface was less smooth, consistent with disruption of tear film stability. While surface cells presented with well-developed microprojections, an increase in the number of cells with fewer microprojections was observed. Moreover, an increase in skin-type keratin K10 and a decrease in transcription factor Pax6 was observed, suggesting an incipient transdifferentiation. Despite this, no evidence of inflammatory dry eye disease was apparent. In addition, Muc4 had no effect on signaling by toll-like receptor Tlr4, unlike reports for MUC1 and MUC16. Results of this study provide the first in vivo evidence for the role of MAMs in transcellular barrier function, tear film stability, apical epithelial cell architecture, and epithelial mucosal differentiation at the ocular surface.
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Affiliation(s)
- Rafael Martinez-Carrasco
- New England Eye Center, Tufts Medical Center and Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Satyanarayan Rachagani
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA
- Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pablo Argüeso
- New England Eye Center, Tufts Medical Center and Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, 02111, USA
- Program in Immunology, Tufts Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA
- Program in Genetics, Molecular & Cellular Biology, Tufts Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA
- Program in Pharmacology & Drug Development, Tufts Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA
| | - M Elizabeth Fini
- New England Eye Center, Tufts Medical Center and Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, 02111, USA.
- Program in Genetics, Molecular & Cellular Biology, Tufts Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA.
- Program in Pharmacology & Drug Development, Tufts Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA.
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20
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Chen YY, Liu H, Li LY, Li LJ, Wang HQ, Song J, Wu YH, Guan J, Xing LM, Wang GJ, Qu W, Liu H, Wang XM, Shao ZH, Fu R. [Role and clinical significance of MUC4 gene mutations in thrombotic events in patients with classic paroxysmal nocturnal hemoglobinuria]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:561-566. [PMID: 37749036 PMCID: PMC10509626 DOI: 10.3760/cma.j.issn.0253-2727.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Indexed: 09/27/2023]
Abstract
Objective: This study aimed to investigate the role and clinical significance of MUC4 gene mutations in thrombotic events in patients with classic paroxysmal nocturnal hemoglobinuria (PNH) patients. Methods: A retrospective analysis was conducted on the clinical data and gene sequencing results of 45 patients with classic PNH admitted to the Department of Hematology, Tianjin Medical University General Hospital, from June 2018 to February 2022. MUC4 gene mutations in patients with classic PNH were summarized, and the risk factors for thrombotic events in these patients were analyzed. Additionally, the effects of MUC4 gene mutations on the cumulative incidence and survival of thrombotic events in patients with classic PNH were determined. Results: The detection rate of MUC4 gene mutations in patients with classic PNH who experienced thrombotic events (thrombotic group) was 68.8% (11/16), which was significantly higher than that in the non-thrombotic group [10.3% (3/29) ] (P<0.001). All mutations occurred in exon 2. MUC4 mutation (OR=20.815, P=0.010) was identified as an independent risk factor for thrombotic events in patients with classic PNH. The cumulative incidence of thrombotic events was 78.6% (11/14) in the MUC4 gene mutation group (mutation group) and 16.1% (5/31) in the non-mutation group, showing a statistically significant difference between the two groups (P<0.001). Survival analysis showed a lower overall survival (OS) rate in the thrombotic group compared with that in the non-thrombotic group [ (34.4±25.2) % vs. (62.7±19.3) % ] (P=0.045). The OS rate of patients was (41.7±29.9) % in the mutation group and (59.1±18.3) % in the non-mutation group (P=0.487) . Conclusion: MUC4 gene mutations are associated with an increased incidence of thrombotic events in classic PNH patients, highlighting their role as independent risk factors for thrombosis in this population. These mutations can be considered a novel predictive factor that aids in evaluating the risk of thrombosis in patients with classic PNH.
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Affiliation(s)
- Y Y Chen
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - H Liu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - L Y Li
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - L J Li
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - H Q Wang
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - J Song
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Y H Wu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - J Guan
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - L M Xing
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - G J Wang
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - W Qu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - H Liu
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - X M Wang
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Z H Shao
- Tianjin Medical University General Hospital, Tianjin 300052, China
| | - R Fu
- Tianjin Medical University General Hospital, Tianjin 300052, China
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21
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Gestrich CK, De Lancy SJ, Kresak A, Sinno MG, Yalley A, Pateva I, Meyerson H, Shetty S, Oduro KA. Mucin 4 (MUC4) Protein is Expressed in B-Acute Lymphoblastic Leukemia (B-ALL) and is restricted to BCR::ABL1 Positive and BCR::ABL-like Subtypes. Hum Pathol 2023; 136:75-83. [PMID: 37023866 DOI: 10.1016/j.humpath.2023.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/25/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023]
Abstract
Mucin 4 (MUC4) is a transmembrane mucin that, like most mucins, is not expressed in normal hematopoietic cells but little is known about its expression in malignant hematopoiesis. B-Acute Lymphoblastic Leukemia (B-ALL) consists of genetically distinct disease subtypes with similarities and differences in gene expression most frequently studied at the mRNA level, which is less amenable to widespread routine clinical use. Here, we demonstrate using immunohistochemistry (IHC) that MUC4 protein is expressed in less than 10% of B-ALL with expression restricted to BCR::ABL1+ and BCR::ABL1-like (CRLF2 rearranged) subtypes of B-ALL (4/13, 31%). None (0/36, 0%) of the remaining B-ALL subtypes expressed MUC4. We compare clinical and pathologic features of MUC4+ and MUC4- BCR::ABL1+/like cases and most significantly report a possible shorter time to relapse for MUC4+ BCR::ABL1 B-ALL that would need to be validated in larger studies. In conclusion, MUC4 is a specific, albeit insensitive, marker for these high-risk subtypes of B-ALL. We propose that MUC4 IHC may be employed diagnostically to rapidly identify these B-ALL subtypes particularly in resource limited settings or when an aspirate sample is not available for ancillary genetic studies.
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Affiliation(s)
- Catherine K Gestrich
- Department of Pathology, University Hospitals Cleveland Medical Center & Rainbow Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Shanelle J De Lancy
- Department of Pathology, University Hospitals Cleveland Medical Center & Rainbow Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA
| | - Adam Kresak
- Department of Pathology, University Hospitals Cleveland Medical Center & Rainbow Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA
| | - Mohamad G Sinno
- Department of Pediatrics, Division of Hematology and Oncology, University Hospitals Rainbow Babies and Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA; Department of Pediatrics, Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix AZ, USA
| | - Akua Yalley
- Department of Medical Laboratory Sciences, School of Biomedical and Allied Health Sciences, University of Ghana, Accra, Ghana
| | - Irina Pateva
- Department of Pediatrics, Division of Hematology and Oncology, University Hospitals Rainbow Babies and Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA
| | - Howard Meyerson
- Department of Pathology, University Hospitals Cleveland Medical Center & Rainbow Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA
| | - Shashirekha Shetty
- Department of Pathology, University Hospitals Cleveland Medical Center & Rainbow Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA
| | - Kwadwo A Oduro
- Department of Pathology, University Hospitals Cleveland Medical Center & Rainbow Children's Hospital & Case Western Reserve University, Cleveland, Ohio, 44106, USA.
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22
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Dan WY, Yang YS, Peng LH, Sun G, Wang ZK. Gastrointestinal microbiome and cholelithiasis: Current status and perspectives. World J Gastroenterol 2023; 29:1589-1601. [PMID: 36970590 PMCID: PMC10037248 DOI: 10.3748/wjg.v29.i10.1589] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 03/06/2023] [Indexed: 03/14/2023] Open
Abstract
Cholelithiasis is a common digestive disease affecting 10% to 15% of adults. It imposes significant global health and financial burdens. However, the pathogenesis of cholelithiasis involves several factors and is incompletely elucidated. In addition to genetic predisposition and hepatic hypersecretion, the pathogenesis of cholelithiasis might involve the gastrointestinal (GI) microbiome, consisting of microorganisms and their metabolites. High-throughput sequencing studies have elucidated the role of bile, gallstones, and the fecal microbiome in cholelithiasis, associating microbiota dysbiosis with gallstone formation. The GI microbiome may drive cholelithogenesis by regulating bile acid metabolism and related signaling pathways. This review examines the literature implicating the GI microbiome in cholelithiasis, specifically gallbladder stones, choledocholithiasis, and asymptomatic gallstones. We also discuss alterations of the GI microbiome and its influence on cholelithogenesis.
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Affiliation(s)
- Wan-Yue Dan
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School, Nankai University, Tianjin 300071, China
| | - Yun-Sheng Yang
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Li-Hua Peng
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Gang Sun
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Zi-Kai Wang
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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23
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Dan WY, Yang YS, Peng LH, Sun G, Wang ZK. Gastrointestinal microbiome and cholelithiasis: Current status and perspectives. World J Gastroenterol 2023; 29:1445-1457. [DOI: 10.3748/wjg.v29.i10.1445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/10/2023] Open
Affiliation(s)
- Wan-Yue Dan
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China,Medical School, Nankai University, Tianjin 300071, China
| | - Yun-Sheng Yang
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Li-Hua Peng
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Gang Sun
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Zi-Kai Wang
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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24
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Jung A, Munõz-López Á, Buchmuller BC, Banerjee S, Summerer D. Imaging-Based In Situ Analysis of 5-Methylcytosine at Low Repetitive Single Gene Loci with Transcription-Activator-Like Effector Probes. ACS Chem Biol 2023; 18:230-236. [PMID: 36693632 PMCID: PMC9942090 DOI: 10.1021/acschembio.2c00857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Transcription-activator-like effectors (TALEs) are programmable DNA binding proteins that can be used for sequence-specific, imaging-based analysis of cellular 5-methylcytosine. However, this has so far been limited to highly repetitive satellite DNA. To expand this approach to the analysis of coding single gene loci, we here explore a number of signal amplification strategies for increasing imaging sensitivity with TALEs. We develop a straightforward amplification protocol and employ it to target the MUC4 gene, which features only a small cluster of repeat sequences. This offers high sensitivity imaging of MUC4, and in costaining experiments with pairs of one TALE selective for unmethylated cytosine and one universal control TALE enables analyzing methylation changes in the target independently of changes in target accessibility. These advancements offer prospects for 5-methylcytosine analysis at coding, nonrepetitive gene loci by the use of designed TALE probe collections.
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Affiliation(s)
- Anne Jung
- Faculty
of Chemistry and Chemical Biology, TU Dortmund
University, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
| | - Álvaro Munõz-López
- Faculty
of Chemistry and Chemical Biology, TU Dortmund
University, Otto-Hahn-Str. 6, 44227 Dortmund, Germany,International
Max Planck Research School of Living Matter, Otto-Hahn-Str. 11, 44227 Dortmund, Germany
| | - Benjamin C. Buchmuller
- Faculty
of Chemistry and Chemical Biology, TU Dortmund
University, Otto-Hahn-Str. 6, 44227 Dortmund, Germany,International
Max Planck Research School of Living Matter, Otto-Hahn-Str. 11, 44227 Dortmund, Germany
| | - Sudakshina Banerjee
- Faculty
of Chemistry and Chemical Biology, TU Dortmund
University, Otto-Hahn-Str. 6, 44227 Dortmund, Germany,International
Max Planck Research School of Living Matter, Otto-Hahn-Str. 11, 44227 Dortmund, Germany
| | - Daniel Summerer
- Faculty
of Chemistry and Chemical Biology, TU Dortmund
University, Otto-Hahn-Str. 6, 44227 Dortmund, Germany,International
Max Planck Research School of Living Matter, Otto-Hahn-Str. 11, 44227 Dortmund, Germany,
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25
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Zhang C, Atri P, Nallasamy P, Parte S, Rauth S, Nimmakayala RK, Marimuthu S, Chirravuri-Venkata R, Bhatia R, Halder S, Shah A, Cox JL, Smith L, Kumar S, Foster JM, Kukreja RC, Seshacharyulu P, Ponnusamy MP, Batra SK. Small molecule inhibitor against onco-mucins disrupts Src/FosL1 axis to enhance gemcitabine efficacy in pancreatic ductal adenocarcinoma. Cancer Lett 2022; 551:215922. [PMID: 36285687 PMCID: PMC10124158 DOI: 10.1016/j.canlet.2022.215922] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 09/09/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022]
Abstract
Mucin MUC4 is an aberrantly expressed oncogene in pancreatic ductal adenocarcinoma (PDAC), yet no pharmacological inhibitors have been identified to target MUC4. Here, we adapted an in silico screening method using the Cancer Therapeutic Response Database (CTRD) to Identify Small Molecule Inhibitors against Mucins (SMIMs). We identified Bosutinib as a candidate drug to target oncogenic mucins among 126 FDA-approved drugs from CTRD screening. Functionally, Bosutinib treatment alone/and in combination with gemcitabine (Gem)/5' fluorouracil (5FU) reduced in vitro viability, migration, and colony formation in multiple PDAC cell lines as well as human PDAC organoid prolifertaion and growth and in vivo xenograft growth. Further, biochemical and molecular analyses showed that Bosutinib exhibited these functional effects by downregulating MUC4 mucin at both transcript and translation levels in a dose- and time-dependent manner. Mechanistically, global transcriptome analysis in PDAC cells upon treatment with Bosutinib revealed disruption of the Src-ERK/AKT-FosL1 pathway, leading to decreased expression of MUC4 and MUC5AC mucins. Taken together, Bosutinib is a promising, novel, and highly potent SMIMs to target MUC4/MUC5AC mucins. This mucin-targeting effect of Bosutinib can be exploited in the future with cytotoxic agents to treat mucinous tumors.
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Affiliation(s)
- Chunmeng Zhang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Palanisamy Nallasamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Seema Parte
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Saravanakumar Marimuthu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushanta Halder
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ashu Shah
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jesse L Cox
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Lynette Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jason M Foster
- Department of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rakesh C Kukreja
- Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA
| | | | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE, USA.
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26
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Guan B, Chai Y, Amantai X, Chen X, Cao X, Yue X. A new sight to explore site-specific N-glycosylation in donkey colostrum milk fat globule membrane proteins with glycoproteomics analysis. Food Res Int 2022; 162:111938. [DOI: 10.1016/j.foodres.2022.111938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/10/2022] [Accepted: 09/12/2022] [Indexed: 11/04/2022]
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27
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Liu Z, Su R, Ahsan A, Liu C, Liao X, Tian D, Su M. Esophageal Squamous Cancer from 4NQO-Induced Mice Model: CNV Alterations. Int J Mol Sci 2022; 23:ijms232214304. [PMID: 36430789 PMCID: PMC9698903 DOI: 10.3390/ijms232214304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Squamous esophageal carcinoma is a common pathological type of esophageal carcinoma around the world. The prognosis of esophageal carcinoma is usually poor and diagnosed at late stages. Recently, research suggested that genomic instability occurred in esophageal cells during the development of esophageal squamous cell carcinoma (ESCC). Identifying prognostic and specific genomic characteristics, especially at the early hyperplasia stage, is critical. Mice were given 4-nitroquinoline 1-oxide (4NQO) with drinking water to induce esophageal cancer. The immortalized human esophageal epithelial cell line (NE2) was also treated with 4NQO. We performed histologic analyses, immunofluorescence, and immunohistochemical staining to detect DNA damage at different time points. Whole-exome sequencing was accomplished on the esophagus tissues at different pathological stages to detect single-nucleotide variants and copy number variation (CNV) in the genome. Our findings indicate that all mice were tumor-forming, and a series of changes from simple hyperplasia (ESSH) to intraepithelial neoplasia (IEN) to esophageal squamous cell carcinoma (ESCC) was seen at different times. The expression of γ-H2AX increased from ESSH to ESCC. In addition, mutations of the Muc4 gene were detected throughout the pathological stages. Furthermore, CNV burden appeared in the esophageal tissues from the beginning of ESSH and accumulated more in cancer with the deepening of the lesions. This study demonstrates that mutations caused by the early appearance of DNA damage may appear in the early stage of malignant tissue before the emergence of atypia. The detection of CNV and mutations of the Muc4 gene may be used as an ultra-early screening indicator for esophageal cancer.
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Affiliation(s)
| | | | | | | | | | | | - Min Su
- Correspondence: ; Fax: +86-0754-88900429
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28
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Haridi A. Identification, diversity and domain structure analysis of mucin and mucin-like genes in sea anemone Actinia tenebrosa. PeerJ 2022; 10:e13292. [PMID: 35539013 PMCID: PMC9080433 DOI: 10.7717/peerj.13292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 03/28/2022] [Indexed: 01/13/2023] Open
Abstract
Background Mucins are part of the glycoprotein family and the main proteinaceous component of mucus. The sea anemone species, Actinia tenebrosa (Phylum Cnidaria) produce large amounts of mucus, which have not been studied in detail. Furthermore, there has only been limited investigation of mucin genes in phylum Cnidaria. Therefore, the aim of current study was to identify and analyse the repertoire mucin genes present in A. tenebrosa and range of other sea anemone species to document their diversity in this group. Methods To achieve this aim, we undertook transcriptome sequencing, assembly, and annotation to identify mucin genes in A. tenebrosa. Results The results from this study demonstrated a diverse repertoire of mucin proteins, including mucin1-like, mucin4-like, and a range of mucin-like genes in the range of sea anemone species examined. The domain structure of the identified mucin genes was found to be consistent with the conserved domains found in the homologous proteins of vertebrate species. The discovery of a diverse range of mucin genes in sea anemone species provided a basic reference for future mucin studies in cnidarians and could lead to research into their application in the pharmacological, clinical, and cosmetic industries.
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29
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Argüeso P. Human ocular mucins: The endowed guardians of sight. Adv Drug Deliv Rev 2022; 180:114074. [PMID: 34875287 PMCID: PMC8724396 DOI: 10.1016/j.addr.2021.114074] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 10/22/2021] [Accepted: 11/30/2021] [Indexed: 01/03/2023]
Abstract
Mucins are an ancient group of glycoproteins that provide viscoelastic, lubricating and hydration properties to fluids bathing wet surfaced epithelia. They are involved in the protection of underlying tissues by forming a barrier with selective permeability properties. The expression, processing and spatial distribution of mucins are often determined by organ-specific requirements that in the eye involve protecting against environmental insult while allowing the passage of light. The human ocular surface epithelia have evolved to produce an extremely thin and watery tear film containing a distinct soluble mucin product secreted by goblet cells outside the visual axis. The adaptation to the ocular environment is notably evidenced by the significant contribution of transmembrane mucins to the tear film, where they can occupy up to one-quarter of its total thickness. This article reviews the tissue-specific properties of human ocular mucins, methods of isolation and detection, and current approaches to model mucin systems recapitulating the human ocular surface mucosa. This knowledge forms the fundamental basis to develop applications with a promising biological and clinical impact.
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Affiliation(s)
- Pablo Argüeso
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States.
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30
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Kshirsagar PG, Gulati M, Junker WM, Aithal A, Spagnol G, Das S, Mallya K, Gautam SK, Kumar S, Sorgen P, Pandey KK, Batra SK, Jain M. Characterization of recombinant β subunit of human MUC4 mucin (rMUC4β). Sci Rep 2021; 11:23730. [PMID: 34887447 PMCID: PMC8660890 DOI: 10.1038/s41598-021-02860-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/03/2021] [Indexed: 12/30/2022] Open
Abstract
MUC4 is a transmembrane mucin expressed on various epithelial surfaces, including respiratory and gastrointestinal tracts, and helps in their lubrication and protection. MUC4 is also aberrantly overexpressed in various epithelial malignancies and functionally contributes to cancer development and progression. MUC4 is putatively cleaved at the GDPH site into a mucin-like α-subunit and a membrane-tethered growth factor-like β-subunit. Due to the presence of several functional domains, the characterization of MUC4β is critical for understanding MUC4 biology. We developed a method to produce and purify multi-milligram amounts of recombinant MUC4β (rMUC4β). Purified rMUC4β was characterized by Far-UV CD and I-TASSER-based protein structure prediction analyses, and its ability to interact with cellular proteins was determined by the affinity pull-down assay. Two of the three EGF-like domains exhibited typical β-fold, while the third EGF-like domain and vWD domain were predominantly random coils. We observed that rMUC4β physically interacts with Ezrin and EGFR family members. Overall, this study describes an efficient and simple strategy for the purification of biologically-active rMUC4β that can serve as a valuable reagent for a variety of biochemical and functional studies to elucidate MUC4 function and generating domain-specific antibodies and vaccines for cancer immunotherapy.
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Affiliation(s)
- Prakash G Kshirsagar
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Mansi Gulati
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Wade M Junker
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA.,Sanguine Diagnostics and Therapeutics, Omaha, NE, USA
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Gaelle Spagnol
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Srustidhar Das
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Kavita Mallya
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Paul Sorgen
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Krishan K Pandey
- Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, St. Louis, MO, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Sanguine Diagnostics and Therapeutics, Omaha, NE, USA. .,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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31
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He M, Li C, Tang W, Kang Y, Zuo Y, Wang Y. Machine learning gene expression predicting model for ustekinumab response in patients with Crohn's disease. Immun Inflamm Dis 2021; 9:1529-1540. [PMID: 34469062 PMCID: PMC8589399 DOI: 10.1002/iid3.506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background Recent studies reported the responses of ustekinumab (UST) for the treatment of Crohn's disease (CD) differ among patients, while the cause was unrevealed. The study aimed to develop a prediction model based on the gene transcription profiling of patients with CD in response to UST. Methods The GSE112366 dataset, which contains 86 CD and 26 normal samples, was downloaded for analysis. Differentially expressed genes (DEGs) were identified first. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were administered. Least absolute shrinkage and selection operator regression analysis was performed to build a model for UST response prediction. Results A total of 122 DEGs were identified. GO and KEGG analyses revealed that immune response pathways are significantly enriched in patients with CD. A multivariate logistic regression equation that comprises four genes (HSD3B1, MUC4, CF1, and CCL11) for UST response prediction was built. The area under the receiver operator characteristic curve for patients in training set and testing set were 0.746 and 0.734, respectively. Conclusions This study is the first to build a gene expression prediction model for UST response in patients with CD and provides valuable data sources for further studies.
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Affiliation(s)
- Manrong He
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chao Li
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wanxin Tang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingxi Kang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yongdi Zuo
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yufang Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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32
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Stergiou N, Urschbach M, Gabba A, Schmitt E, Kunz H, Besenius P. The Development of Vaccines from Synthetic Tumor-Associated Mucin Glycopeptides and their Glycosylation-Dependent Immune Response. CHEM REC 2021; 21:3313-3331. [PMID: 34812564 DOI: 10.1002/tcr.202100182] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 10/31/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022]
Abstract
Tumor-associated carbohydrate antigens are overexpressed as altered-self in most common epithelial cancers. Their glycosylation patterns differ from those of healthy cells, functioning as an ID for cancer cells. Scientists have been developing anti-cancer vaccines based on mucin glycopeptides, yet the interplay of delivery system, adjuvant and tumor associated MUC epitopes in the induced immune response is not well understood. The current state of the art suggests that the identity, abundancy and location of the glycans on the MUC backbone are all key parameters in the cellular and humoral response. This review shares lessons learned by us in over two decades of research in glycopeptide vaccines. By bridging synthetic chemistry and immunology, we discuss efforts in designing synthetic MUC1/4/16 vaccines and focus on the role of glycosylation patterns. We provide a brief introduction into the mechanisms of the immune system and aim to promote the development of cancer subunit vaccines.
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Affiliation(s)
- Natascha Stergiou
- Radionuclide Center, Radiology and Nuclear medicine Amsterdam UMC, VU University, De Boelelaan 1085c, 1081 HV, Amsterdam, the Netherlands
| | - Moritz Urschbach
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
| | - Adele Gabba
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
| | - Edgar Schmitt
- Institute of Immunology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Horst Kunz
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
| | - Pol Besenius
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany
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33
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Athmane N, Williamson I, Boyle S, Biddie SC, Bickmore WA. MUC4 is not expressed in cell lines used for live cell imaging. Wellcome Open Res 2021; 6:265. [PMID: 34796278 PMCID: PMC8567686 DOI: 10.12688/wellcomeopenres.17229.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/17/2021] [Indexed: 11/20/2022] Open
Abstract
Background: The ability to visualise specific mammalian gene loci in living cells is important for understanding the dynamic processes linked to transcription. However, some of the tools used to target mammalian genes for live cell imaging, such as dCas9, have been reported to themselves impede processes linked to transcription. The MUC4 gene is a popular target for live cell imaging studies due to the repetitive nature of sequences within some exons of this gene. Methods: We set out to compare the impact of dCas9 and TALE-based imaging tools on MUC4 expression, including in human cell lines previously reported as expressing MUC4. Results: We were unable to detect MUC4 mRNA in these cell lines. Moreover, analysis of publicly available data for histone modifications associated with transcription, and data for transcription itself, indicate that neither MUC4, nor any of the mucin gene family are significantly expressed in the cell lines where dCas9 targeting has been reported to repress MUC4 and MUC1 expression, or in the cell lines where dCas13 has been used to report MUC4 RNA detection in live cells. Conclusions: Methods for visualising specific gene loci and gene transcripts in live human cells are very challenging. Our data suggest that care should be given to the choice of the most appropriate cell lines for these analyses and that orthogonal methods of assaying gene expression be carefully compared.
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Affiliation(s)
- Naouel Athmane
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Iain Williamson
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Shelagh Boyle
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Simon C. Biddie
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Wendy A. Bickmore
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
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34
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Nam H, Lee IH, Sa JK, Kim SS, Pyeon HJ, Lee KH, Lee K, Lee SH, Joo KM. Effects of Long-Term In Vitro Expansion on Genetic Stability and Tumor Formation Capacity of Stem Cells. Stem Cell Rev Rep 2021; 18:241-257. [PMID: 34738209 DOI: 10.1007/s12015-021-10290-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2021] [Indexed: 12/30/2022]
Abstract
Stem cell therapeutics are emerging as novel alternative treatments for various neurodegenerative diseases based on their regenerative potentials. However, stem cell transplantation might have side effects such as tumor formation that limit their clinical applications. Especially, in vitro expansion of stem cells might provoke genetic instability and tumorigenic potential. To address this issue, we analyzed genomic alterations of adult human multipotent neural cells (ahMNCs), a type of human adult neural stem cells, after a long-term in vitro culture process (passage 15) using sensitive analysis techniques including karyotyping, array comparative genomic hybridization (aCGH), and whole exome sequencing (WES). Although karyotyping did not find any major abnormalities in chromosomal number or structure, diverse copy number variations (CNVs) and genetic mutations were detected by aCGH and WES in all five independent ahMNCs. However, the number of CNVs and genetic mutations did not increase and many of them did not persist as in vitro culture progressed. Although most observed CNVs and genetic mutations were not shared by all five ahMNCs, nonsynonymous missense mutations at MUC4 were found in three out of five long-term cultured ahMNC lines. The genetic instability did not confer in vivo tumorigenic potential to ahMNCs. Collectively, these results indicate that, although genetic instability can be induced by long-term in vitro expansion of stem cells, it is not sufficient to fully exert tumor formation capacity of stem cells. Other functional effects of such genetic instability need to be further elucidated.
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Affiliation(s)
- Hyun Nam
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Suwon, Gyeonggi-do, 16419, South Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.,Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea
| | - In-Hee Lee
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Jason K Sa
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea
| | - Sung Soo Kim
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Suwon, Gyeonggi-do, 16419, South Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.,Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea
| | - Hee-Jang Pyeon
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Suwon, Gyeonggi-do, 16419, South Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.,Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea
| | - Kee Hang Lee
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Suwon, Gyeonggi-do, 16419, South Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.,Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea
| | - Kyunghoon Lee
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Suwon, Gyeonggi-do, 16419, South Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Sun-Ho Lee
- Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea. .,Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea. .,Biomedical Institute for Convergence at Sungkyunkwan University (BICS), Sungkyunkwan University, Suwon, 16419, South Korea. .,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
| | - Kyeung Min Joo
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Suwon, Gyeonggi-do, 16419, South Korea. .,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea. .,Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea. .,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, South Korea. .,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
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35
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Wang X, Shirazi F, Yan W, Liu X, Wang H, Orlowski RZ, Wang H. Mucin 20 modulates proteasome capacity through c-Met signalling to increase carfilzomib sensitivity in mantle cell lymphoma. J Cell Mol Med 2021; 25:10164-10174. [PMID: 34651428 PMCID: PMC8572801 DOI: 10.1111/jcmm.16953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 09/08/2021] [Accepted: 09/11/2021] [Indexed: 11/28/2022] Open
Abstract
Mantle cell lymphoma (MCL) is a haematologic malignancy. The proteasome inhibitor (PI) bortezomib has been approved to treat MCL, but resistance has emerged through mechanisms that remain unclear. This study aimed to explore the mechanism of PI resistance in MCL and identify new targets for this patient subgroup. Carfilzomib‐resistant (CR) MCL cell lines and primary samples were used for both in vitro and in vivo experiments to identify gene expression and explore their related signalling pathways. We first identified mucin 20 (MUC20) suppression in carfilzomib‐resistant MCL models. MUC20 overexpression sensitized cells to carfilzomib in vitro and in vivo. MUC20 expression was inversely related to activation of c‐Met and the downstream p44/42 MAPK pathway. c‐Met activation with hepatocyte growth factor (HGF) induced PI resistance, while c‐Met inhibition restored PI sensitivity. Carfilzomib resistance and depressed MUC20 expression were associated with enhanced proteasome activity and higher expression of proteassemblin (POMP), a chaperone for catalytically active proteasome assembly. c‐Met and POMP were associated through binding and induction of MAPK‐regulated ELK1 to the POMP promoter. Our data reveal that c‐Met signalling activation enhanced proteasome capacity as a mechanism of PI resistance, and MUC20 expression may be a useful biomarker for PI therapy.
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Affiliation(s)
- Xiaobin Wang
- The Departments of Hematology, Shengjing Hospital, China Medical University, Shenyang, China
| | - Fazal Shirazi
- The Departments of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wei Yan
- The Departments of Hematology, Shengjing Hospital, China Medical University, Shenyang, China
| | - Xiaoyu Liu
- The Departments of Hematology, Shengjing Hospital, China Medical University, Shenyang, China
| | - Hua Wang
- The Departments of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Robert Z Orlowski
- The Departments of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Huihan Wang
- The Departments of Hematology, Shengjing Hospital, China Medical University, Shenyang, China
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36
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Athmane N, Williamson I, Boyle S, Biddie SC, Bickmore WA. MUC4 is not expressed in cell lines used for live cell imaging. Wellcome Open Res 2021; 6:265. [PMID: 34796278 PMCID: PMC8567686 DOI: 10.12688/wellcomeopenres.17229.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2021] [Indexed: 11/20/2022] Open
Abstract
Background: The ability to visualise specific mammalian gene loci in living cells is important for understanding the dynamic processes linked to transcription. However, some of the tools used to target mammalian genes for live cell imaging, such as dCas9, have been reported to themselves impede processes linked to transcription. The MUC4 gene is a popular target for live cell imaging studies due to the repetitive nature of sequences within some exons of this gene. Methods: We set out to compare the impact of dCas9 and TALE-based imaging tools on MUC4 expression, including in human cell lines previously reported as expressing MUC4. Results: We were unable to detect MUC4 mRNA in these cell lines. Moreover, analysis of publicly available data for histone modifications associated with transcription, and data for transcription itself, indicate that neither MUC4, nor any of the mucin gene family are significantly expressed in the cell lines where dCas9 targeting has been reported to repress MUC4 and MUC1 expression, or in the cell lines where dCas13 has been used to report MUC4 RNA detection in live cells. Conclusions: Methods for visualising specific gene loci and gene transcripts in live human cells are very challenging. Our data suggest that care should be given to the choice of the most appropriate cell lines for these analyses and that orthogonal methods of assaying gene expression be carefully compared.
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Affiliation(s)
- Naouel Athmane
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Iain Williamson
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Shelagh Boyle
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Simon C. Biddie
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
| | - Wendy A. Bickmore
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, EH42XU, UK
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37
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Tan X, Zhang L, Li T, Zhan J, Qiao K, Wu H, Sun S, Huang M, Zhang F, Zhang M, Li C, Li R, Pan H. Lgr4 Regulates Oviductal Epithelial Secretion Through the WNT Signaling Pathway. Front Cell Dev Biol 2021; 9:666303. [PMID: 34631693 PMCID: PMC8497904 DOI: 10.3389/fcell.2021.666303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
The WNT signaling pathway plays a crucial role in oviduct/fallopian development. However, the specific physiological processes regulated by the WNT pathway in the fallopian/oviduct function remain obscure. Benefiting from the Lgr4 knockout mouse model, we report the regulation of oviduct epithelial secretion by LGR4. Specifically, the loss of Lgr4 altered the mouse oviduct size and weight, severely reduced the number of oviductal epithelial cells, and ultimately impaired the epithelial secretion. These alterations were mediated by a failure of CTNNB1 protein accumulation in the oviductal epithelial cytoplasm, by the modulation of WNT pathways, and subsequently by a profound change of the gene expression profile of epithelial cells. In addition, selective activation of the WNT pathway triggered the expression of steroidogenic genes, like Cyp11a1 and 3β-Hsd1, through the activation of the transcriptional factor NR5A2 in an oviduct primary cell culture system. As demonstrated, the LGR4 protein modulates a WNT-NR5A2 signaling cascade facilitating epithelial secretory cell maturation and steroidogenesis to safeguard oviduct development and function in mice.
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Affiliation(s)
- Xue Tan
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Lingling Zhang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Tianqi Li
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Jianmin Zhan
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Kun Qiao
- Center for Reproductive Medicine, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Haili Wu
- Shanghai Endangered Species Conservation and Research Centre, Shanghai Zoo, Shanghai, China
| | - Shenfei Sun
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Meina Huang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Fangxi Zhang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Meixing Zhang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Changwei Li
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases With Integrated Chinese-Western Medicine, Ruijin Hospital, Shanghai Institute of Traumatology and Orthopedics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Runsheng Li
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Hongjie Pan
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
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38
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Thompson CM, Cannon A, West S, Ghersi D, Atri P, Bhatia R, Smith L, Rachagani S, Wichman C, Kumar S, Batra SK. Mucin Expression and Splicing Determine Novel Subtypes and Patient Mortality in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2021; 27:6787-6799. [PMID: 34615717 DOI: 10.1158/1078-0432.ccr-21-1591] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/15/2021] [Accepted: 10/04/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy demonstrating aberrant and progressive expression of mucins. The contribution of individual mucins has been extensively investigated in PDAC; however, comprehensive mucin profiling including splice variants in PDAC tumors has not been reported. EXPERIMENTAL DESIGN Using publicly available RNA sequencing (RNA-seq) datasets, we assess the expression of mucin family members and their splice variants (SV) in PDAC tumor samples for the first time. Mucin SVs that are correlated with PDAC patient survival are validated in a cohort of patient tumor samples. Further, we use computational methods to derive novel pancreatic tumor subtypes using mucin expression signatures and their associated activated pathways. RESULTS Principal component analysis identified four novel mucin-based PDAC subtypes. Pathway analysis implicated specific biological signatures for each subtype, labeled (i) immune activated, (ii) progressive, (iii) pancreatitis-initiated, and (iv) anti-inflammatory/PanIN-initiated. Assessing mucin SVs, significantly longer survival is observed with higher expression of 4 MUC1 and 1 MUC13 SVs, whereas patients expressing 2 MUC4 and 1 MUC16 SVs had shorter survival. Using a whole-transcriptome correlation, a three-gene panel, including ESRP2, PTK6, and MAGEH1, is designated to assess PDAC tumor sample cellularity by PCR. One MUC4 SV and one MUC13 SV are quantified in a separate PDAC patient cohort, and their effects on survival are experimentally validated. CONCLUSIONS Altogether, we demonstrate the unique expression pattern of mucins, four mucin-based PDAC subtypes, and the contribution of MUC1, MUC4, and MUC16 SVs in PDAC patient survival.
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Affiliation(s)
- Christopher M Thompson
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Andrew Cannon
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Sean West
- School of Interdisciplinary Informatics, College of Information Science and Technology, University of Nebraska, Omaha, Nebraska
| | - Dario Ghersi
- School of Interdisciplinary Informatics, College of Information Science and Technology, University of Nebraska, Omaha, Nebraska
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Lynette Smith
- Department of Biostatistics, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Satyayanarayana Rachagani
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Christopher Wichman
- Department of Biostatistics, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. .,The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
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Wang X, Zoccola D, Liew YJ, Tambutte E, Cui G, Allemand D, Tambutte S, Aranda M. The Evolution of Calcification in Reef-Building Corals. Mol Biol Evol 2021; 38:3543-3555. [PMID: 33871620 PMCID: PMC8382919 DOI: 10.1093/molbev/msab103] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Corals build the structural foundation of coral reefs, one of the most diverse and productive ecosystems on our planet. Although the process of coral calcification that allows corals to build these immense structures has been extensively investigated, we still know little about the evolutionary processes that allowed the soft-bodied ancestor of corals to become the ecosystem builders they are today. Using a combination of phylogenomics, proteomics, and immunohistochemistry, we show that scleractinian corals likely acquired the ability to calcify sometime between ∼308 and ∼265 Ma through a combination of lineage-specific gene duplications and the co-option of existing genes to the calcification process. Our results suggest that coral calcification did not require extensive evolutionary changes, but rather few coral-specific gene duplications and a series of small, gradual optimizations of ancestral proteins and their co-option to the calcification process.
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Affiliation(s)
- Xin Wang
- Biological and Environmental Sciences & Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Red Sea Research Center (RSRC), Thuwal, Saudi Arabia
| | - Didier Zoccola
- Marine Biology Department, Centre Scientifique de Monaco, Monaco, Monaco
| | - Yi Jin Liew
- Biological and Environmental Sciences & Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Red Sea Research Center (RSRC), Thuwal, Saudi Arabia
| | - Eric Tambutte
- Marine Biology Department, Centre Scientifique de Monaco, Monaco, Monaco
| | - Guoxin Cui
- Biological and Environmental Sciences & Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Red Sea Research Center (RSRC), Thuwal, Saudi Arabia
| | - Denis Allemand
- Marine Biology Department, Centre Scientifique de Monaco, Monaco, Monaco
| | - Sylvie Tambutte
- Marine Biology Department, Centre Scientifique de Monaco, Monaco, Monaco
| | - Manuel Aranda
- Biological and Environmental Sciences & Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Red Sea Research Center (RSRC), Thuwal, Saudi Arabia
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Mansour K, Elwi DA, Khalifa SE, Abdelmonem Ibrahim H. Immunohistochemical Expression of MUC4 in Different Meningioma Subtypes in Comparison to Some Mesenchymal Non-Meningothelial Tumors. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Meningiomas are the most common primary tumors of the central nervous system worldwide. Routinely used immunohistochemical markers for diagnosis of confusing meningioma cases as epithelial membrane antigen lack specificity and sensitivity. MUC4 is glycosylated membrane-associated mucin expressed by normal epithelia and many cancers. However, it is recently noticed to be expressed in meningiomas.
AIM: Intensity of MUC4 expression is needed to be verified whether it is the same among different subtypes or not.
MATERIALS AND METHODS: Fifty cases of different intracranial meningioma subtypes and thirty cases of mesenchymal nonmeningothelial tumors were immunohistochemically stained with MUC4 antibody. The results of MUC4 expression intensity were associated with some clinical and pathological parameters.
RESULTS: Most studied meningioma cases (84%) showed positive MUC4 expression. Meningothelial meningioma subtype showed characteristic pattern of diffuse and moderate to strong MUC4 staining. While fibroblastic meningioma showed mostly negative staining pattern and focal weak staining pattern if positive. A statistically significant relationship was detected between tumor subtype and intensity of MUC4 expression. On contrary, most included mesenchymal cases were MUC4 negative with statistical significance. Hence, the sensitivity of MUC4 as diagnostic marker for meningioma was 84%, while the specificity was 93.3%. Furthermore, meningioma histologic subtype showed significant relationship with age.
CONCLUSION: The current study results suggest that MUC4 could be used as meningioma diagnostic marker with some limitations. Moreover, meningioma should be included in the differential diagnosis of MUC4 positive tumors.
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Abstract
Angiomatoid fibrous histiocytoma (AFH) is a rarely metastasizing neoplasm that typically occurs in the deep dermis and subcutis of the extremities of young patients, characterized by a t(2;22) translocation involving EWSR1 and CREB1. Because of its distinctive histologic features, the diagnosis of AFH is generally straightforward, although the immunohistochemistry (IHC) findings are relatively nonspecific. We recently encountered a case of primary cranial AFH that showed strong MUC4 IHC expression, which has not yet been reported previously. Prompted by this surprising finding, we investigated MUC4 expression in a series of AFH to evaluate this potential diagnostic pitfall. The expression of ALK by IHC, recently discovered in AFH, was also assessed in this study. We also analyzed EWSR1 rearrangement by fluorescence in situ hybridization using a dual color break-apart probe to confirm the diagnosis. The results showed MUC4 expression in 22.2% of AFH cases (4/18 cases), demonstrating a variable intensity of cytoplasmic staining. Most notably, one of the positive cases showed strong and diffuse expression. ALK IHC expression was observed in 17 of 18 cases (94.4%), usually in a diffuse and strong cytoplasmic pattern. EWSR1 rearrangement was demonstrated by fluorescence in situ hybridization in 81.2% of cases (13 of 16), including all the MUC4-positive cases. Our results indicate that although the significance of MUC4 expression in AFH is unknown, it is important to be aware that a subset of AFH can express the protein by IHC, expanding a variety of MUC4-positive mesenchymal tumors.
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Kim YD, Choi YS, Na HG, Song SY, Bae CH. MUC4 Silencing Inhibits TGF-β1-Induced Epithelial-Mesenchymal Transition via the ERK1/2 Pathway in Human Airway Epithelial NCI-H292 Cells. Mol Biol 2021; 55:565-572. [DOI: 10.1134/s0026893321030079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/17/2020] [Accepted: 08/19/2020] [Indexed: 07/25/2023]
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Martinez-Carrasco R, Argüeso P, Fini ME. Membrane-associated mucins of the human ocular surface in health and disease. Ocul Surf 2021; 21:313-330. [PMID: 33775913 PMCID: PMC8328898 DOI: 10.1016/j.jtos.2021.03.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/02/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023]
Abstract
Mucins are a family of high molecular weight, heavily-glycosylated proteins produced by wet epithelial tissues, including the ocular surface epithelia. Densely-packed O-linked glycan chains added post-translationally confer the biophysical properties of hydration, lubrication, anti-adhesion and repulsion. Membrane-associated mucins (MAMs) are the distinguishing components of the mucosal glycocalyx. At the ocular surface, MAMs maintain wetness, lubricate the blink, stabilize the tear film, and create a physical barrier to the outside world. In addition, it is increasingly appreciated that MAMs function as cell surface receptors that transduce information from the outside to the inside of the cell. Recently, our team published a comprehensive review/perspectives article for molecular scientists on ocular surface MAMs, including previously unpublished data and analyses on two new genes MUC21 and MUC22, as well as new MAM functions and biological roles, comparing human and mouse (PMID: 31493487). The current article is a refocus for the audience of The Ocular Surface. First, we update the gene and protein information in a more concise form, and include a new section on glycosylation. Next, we discuss biological roles, with some new sections and further updating from our previous review. Finally, we provide a new chapter on MAM involvement in ocular surface disease. We end this with discussion of an emerging mechanism responsible for damage to the epithelia and their mucosal glycocalyces: the unfolded protein response (UPR). The UPR offers a novel target for therapeutic intervention.
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Affiliation(s)
- Rafael Martinez-Carrasco
- Department of Ophthalmology, Tufts University School of Medicine at New England Eye Center, Tufts Medical Center, Boston, MA, 02111, USA.
| | - Pablo Argüeso
- Department of Ophthalmology, Harvard Medical School at Schepens Eye Research Institute of Mass, Eye and Ear, Boston, MA, 02114, USA.
| | - M Elizabeth Fini
- Department of Ophthalmology, Tufts University School of Medicine at New England Eye Center, Tufts Medical Center: Program in Pharmacology & Drug Development, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, O2111, USA.
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Giamougiannis P, Martin-Hirsch PL, Martin FL. The evolving role of MUC16 (CA125) in the transformation of ovarian cells and the progression of neoplasia. Carcinogenesis 2021; 42:327-343. [PMID: 33608706 DOI: 10.1093/carcin/bgab010] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/19/2021] [Accepted: 02/15/2021] [Indexed: 12/23/2022] Open
Abstract
MUC16 (the cancer antigen CA125) is the most commonly used serum biomarker in epithelial ovarian cancer, with increasing levels reflecting disease progression. It is a transmembrane glycoprotein with multiple isoforms, undergoing significant changes through the metastatic process. Aberrant glycosylation and cleavage with overexpression of a small membrane-bound fragment consist MUC16-related mechanisms that enhance malignant potential. Even MUC16 knockdown can induce an aggressive phenotype but can also increase susceptibility to chemotherapy. Variable MUC16 functions help ovarian cancer cells avoid immune cytotoxicity, survive inside ascites and form metastases. This review provides a comprehensive insight into MUC16 transformations and interactions, with description of activated oncogenic signalling pathways, and adds new elements on the role of its differential glycosylation. By following the journey of the molecule from pre-malignant states to advanced stages of disease it demonstrates its behaviour, in relation to the phenotypic shifts and progression of ovarian cancer. Additionally, it presents proposed differences of MUC16 structure in normal/benign conditions and epithelial ovarian malignancy.
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Affiliation(s)
- Panagiotis Giamougiannis
- Department of Gynaecological Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.,School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, UK
| | - Pierre L Martin-Hirsch
- Department of Gynaecological Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
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Marimuthu S, Rauth S, Ganguly K, Zhang C, Lakshmanan I, Batra SK, Ponnusamy MP. Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression. Cancer Metastasis Rev 2021; 40:575-588. [PMID: 33813658 PMCID: PMC9635594 DOI: 10.1007/s10555-021-09959-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023]
Abstract
Mucins are high-molecular-weight glycoproteins dysregulated in aggressive cancers. The role of mucins in disease progression, tumor proliferation, and chemotherapy resistance has been studied extensively. This article provides a comprehensive review of mucin's function as a physical barrier and the implication of mucin overexpression in impeded drug delivery to solid tumors. Mucins regulate the epithelial to mesenchymal transition (EMT) of cancer cells via several canonical and non-canonical oncogenic signaling pathways. Furthermore, mucins play an extensive role in enriching and maintaining the cancer stem cell (CSC) population, thereby sustaining the self-renewing and chemoresistant cellular pool in the bulk tumor. It has recently been demonstrated that mucins regulate the metabolic reprogramming during oncogenesis and cancer progression, which account for tumor cell survival, proliferation, and drug-resistance. This review article focuses on delineating mucin's role in oncogenic signaling and aberrant regulation of gene expressions, culminating in CSC maintenance, metabolic rewiring, and development of chemoresistance, tumor progression, and metastasis.
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Affiliation(s)
- Saravanakumar Marimuthu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Chunmeng Zhang
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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Liu L, Kshirsagar P, Christiansen J, Gautam SK, Aithal A, Gulati M, Kumar S, Solheim JC, Batra SK, Jain M, Wannemuehler MJ, Narasimhan B. Polyanhydride nanoparticles stabilize pancreatic cancer antigen MUC4β. J Biomed Mater Res A 2021; 109:893-902. [PMID: 32776461 PMCID: PMC8100985 DOI: 10.1002/jbm.a.37080] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer (PC) is one of the most lethal malignancies and represents an increasing and challenging threat, especially with an aging population. The identification of immunogenic PC-specific upregulated antigens and an enhanced understanding of the immunosuppressive tumor microenvironment have provided opportunities to enable the immune system to recognize cancer cells. Due to its differential upregulation and functional role in PC, the transmembrane mucin MUC4 is an attractive target for immunotherapy. In the current study we characterized the antigen stability, antigenicity and release kinetics of a MUC4β-nanovaccine to guide further optimization and, in vivo evaluation. Amphiphilic polyanhydride copolymers based on 20 mol % 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane and 80 mol % 1,6-bis(p-carboxyphenoxy)hexane were used to synthesize nanoparticles. Structurally stable MUC4β protein was released from the particles in a sustained manner and characterized by gel electrophoresis and fluorescence spectroscopy. Modest levels of protein degradation were observed upon release. The released protein was also analyzed by MUC4β-specific monoclonal antibodies using ELISA and showed no significant loss of epitope availability. Further, mice immunized with multiple formulations of combination vaccines containing MUC4β-loaded nanoparticles generated MUC4β-specific antibody responses. These results indicate that polyanhydride nanoparticles are viable MUC4β vaccine carriers, laying the foundation for evaluation of this platform for PC immunotherapy.
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Affiliation(s)
- Luman Liu
- Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa
| | - Prakash Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - John Christiansen
- Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, Iowa
| | - Shailendra K. Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Mansi Gulati
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Joyce C. Solheim
- Nanovaccine Institute, Iowa State University, Ames, Iowa
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
- Nanovaccine Institute, Iowa State University, Ames, Iowa
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
- Nanovaccine Institute, Iowa State University, Ames, Iowa
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Michael J. Wannemuehler
- Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, Iowa
- Nanovaccine Institute, Iowa State University, Ames, Iowa
| | - Balaji Narasimhan
- Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa
- Nanovaccine Institute, Iowa State University, Ames, Iowa
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Choi TY, Kim JH, Jo S, Lee S, Na HG, Choi YS, Song SY, Kim YD, Bae CH. Ginsenoside Rb1 Attenuates TGF-β1-Induced MUC4/5AC Expression and Epithelial-Mesenchymal Transition in Human Airway Epithelial Cells. KOREAN JOURNAL OF OTORHINOLARYNGOLOGY-HEAD AND NECK SURGERY 2021; 64:232-239. [DOI: 10.3342/kjorl-hns.2020.00150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/01/2020] [Indexed: 07/25/2023]
Abstract
Background and Objectives Ginsenoside Rb1 is the main metabolite of Panax ginseng. It is known to have many beneficial properties including anti-inflammatory, antitumoral and antioxidant effects. However, the therapeutic effects of ginenoside Rb1 on inflammatory airway diseases have not been elucidated. Therefore, we investigated the effects of ginsenoside Rb1 on the TGF-β1-induced mucin gene expression and epithelial-mesenchymal transition (EMT) in human airway epithelial cells.Materials and Method We evaluated the effects of ginsenoside Rb1 on the changes of MUC4, MUC5AC, occludin, claudin 4, claudin 18, neural (N)-cadherin, and epithelial (E)-cadherin expression by TGF-β1 in NCI-H292 cells using reverse, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and western blot.Results TGF-β1 significantly increased MUC4/5AC expression. Rb1 inhibited TGF-β1- induced MUC4/5AC expression. In addition, TGF-β1 significantly attenuated occludin, claudin 18, and E-cadherin expressions but induced claudin 4 and N-cadherin expressions. On the other hand, Rb1 reversed changes in the TGF-β1- mediated expressions of cell junction molecules.Conclusion These results suggest that ginsenoside Rb1 attenuates TGF-β1-induced MUC4/5AC expressions and EMT in the human airway epithelial cells. These findings are important data demonstrating the potential of ginsenoside Rb1 as a therapeutic agent for inflammatory airway diseases.
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Liu B, Wang F, Chen L, Xin Y, Liu L, Wu D, Li W. Effects of High-Fat Diet on Carcinogen-Induced Pancreatic Cancer and Intestinal Microbiota in C57BL/6 Wild-Type Mice. Pancreas 2021; 50:564-570. [PMID: 33939670 DOI: 10.1097/mpa.0000000000001797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES High-fat diet has been considered a risk factor for the development of pancreatic cancer. It is also shown to significantly impact composition and dysbiosis of gut microbiota in both humans and animals. However, there is little information on the effect of high-fat diet on the development of pancreatic cancer or upon the gut microbiota of patients with pancreatic cancer in humans or animal models. METHODS In this study, the effect of high-fat diet on cancer pathology and the gut microbiota was investigated by a carcinogen-induced pancreatic cancer mouse model. RESULTS Compared with carcinogen alone, mice with high-fat diet and carcinogen showed more obvious pathological changes in pancreatic tissue; increased levels of proinflammatory cytokine tumor necrosis factor-α, interleukin-6, interleukin-10, and carbohydrate antigen 242; and increased expression of cancer-associated biomarkers mucin-4 and claudin-4 in pancreatic tissue. Moreover, there is a significant change in the gut microbiota between the carcinogen group and the carcinogen with high-fat diet group. We identified that Johnsonella ignava especially existed in the carcinogen with high-fat diet group, which may contribute to pancreatic cancer development. CONCLUSIONS Our results revealed that high-fat diet changed the composition of the gut microbiota and was involved in carcinogen-induced pancreatic cancer progression.
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Affiliation(s)
- Beibei Liu
- From the Department of Surgery, Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | | | | | - Yi Xin
- Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
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Warmke LM, Meis JM. Sclerosing Epithelioid Fibrosarcoma: A Distinct Sarcoma With Aggressive Features. Am J Surg Pathol 2021; 45:317-328. [PMID: 32769431 DOI: 10.1097/pas.0000000000001559] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Since its original description in 1995, the concept of sclerosing epithelioid fibrosarcoma (SEF) as a distinctive tumor has evolved in the literature. Subsequent studies suggested that the presence of low grade fibromyxoid sarcoma (LGFMS)-like zones, occasional FUS gene rearrangements, and immunoreactivity for MUC4 all pointed to a close inter-relationship with LGFMS; however, more recent studies showed that SEF is genetically distinct from LGFMS with predominantly EWSR1-CREB3L1 fusion and complex secondary genomic alterations. To better understand the relationship between these tumors, we studied 51 cases of SEF, the largest reported series to date, and directly compared them to a previously published series of LGFMS from the same institution. The male-to-female ratio was 1.4:1 with a median age of 45 years. Tumors occurred primarily in the lower extremity (12), intra-abdominal area/visceral organs (9) and chest wall/paraspinal region (9) with a median size of 8.2 cm. The median follow-up was 49 months in 45 patients: 12 developed local recurrences and 36 developed metastases, mainly to lung and bone. Molecular studies showed EWSR1 gene rearrangement in 13 cases, 3' deletion of EWSR1 in 6, monosomy for EWSR1 in 2; FUS gene rearrangements in 3; EWSR1-CREB3L1 fusion in 7; EWSR1-CREB3L2 fusion in 1; and YAP1-KMT2A fusion in 2. Overall survival of SEF was significantly less compared with LGFMS (P≤0.0001). These results indicate that SEF is a distinct sarcoma that behaves more aggressively than LGFMS with a shorter survival, higher metastatic rate, and greater propensity to involve deep soft tissue and bone.
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Affiliation(s)
- Laura M Warmke
- Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
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50
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Terra SBSP, Roden AC, Aubry MC, Yi ESJ, Boland JM. Utility of Immunohistochemistry for MUC4 and GATA3 to Aid in the Distinction of Pleural Sarcomatoid Mesothelioma From Pulmonary Sarcomatoid Carcinoma. Arch Pathol Lab Med 2021; 145:208-213. [PMID: 33501493 DOI: 10.5858/arpa.2019-0647-oa] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Distinguishing pulmonary sarcomatoid carcinoma from pleural sarcomatoid mesothelioma is challenging because of overlapping histology, immunophenotype, and clinical features. Reliable immunohistochemical markers to aid in this distinction would be very valuable. Recent studies have proposed that MUC4 expression is common in sarcomatoid carcinoma but not in sarcomatoid mesothelioma, with the converse pattern reported for GATA3. OBJECTIVE.— To further explore the utility of MUC4 and GATA3 in distinguishing pulmonary sarcomatoid carcinoma from sarcomatoid mesothelioma. DESIGN.— Well-characterized cases of sarcomatoid carcinoma (n = 32) and sarcomatoid mesothelioma (n = 64) were included. Diagnoses were confirmed by thoracic pathologists with incorporation of immunophenotype, clinical, and radiographic features. Whole-tissue sections were stained for GATA3 and MUC4. RESULTS.— Patients with sarcomatoid carcinoma and sarcomatoid mesothelioma had similar mean age and male predominance. GATA3 was positive in 63 of 64 sarcomatoid mesotheliomas (98%; 42 diffuse, 16 patchy, 5 focal), and 15 of 32 sarcomatoid carcinomas (47%; 3 diffuse, 8 patchy, 4 focal). MUC4 was positive in 2 of 64 sarcomatoid mesotheliomas (3%; 1 patchy, 1 focal), and in 12 of 32 sarcomatoid carcinomas (38%; 5 diffuse, 6 patchy, 1 focal). CONCLUSIONS.— Diffuse GATA3 expression favors sarcomatoid mesothelioma over sarcomatoid carcinoma, which rarely shows diffuse expression (sensitivity and specificity of diffuse staining 66% and 94%, respectively). Focal and patchy GATA3 expression is observed in both tumor types, and therefore is not helpful in this distinction. Sensitivity of MUC4 for sarcomatoid carcinoma was low in our cohort, positive in only 38% with frequent patchy staining, but it was quite specific.
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Affiliation(s)
- Simone B S P Terra
- From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Anja C Roden
- From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Marie Christine Aubry
- From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Eunhee S Joanne Yi
- From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jennifer M Boland
- From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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