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Okuno R, Nakada S, Tonomura K, Aso Y, Takeshita D, Ohnuma T, Tanaka T. β1,6-Selective Enzymatic N-Acetylglucosamination Catalyzed by the Family GH84 N-Acetyl-β-D-glucosaminidase from Bacteroides thetaiotaomicron and its Glycosyl Acceptor Specificity. Chem Asian J 2025:e202500142. [PMID: 40195893 DOI: 10.1002/asia.202500142] [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] [Received: 01/29/2025] [Revised: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 04/09/2025]
Abstract
The chemoenzymatic synthesis of oligosaccharides presents a highly attractive methodology with significant potential for diverse applications, particularly through using various glycosidases. In this study, the O-glycan core 6 disaccharide moiety, GlcNAcβ1-6GalNAc, was successfully synthesized via enzymatic glycosylation using an N-acetyl-β-D-glucosaminidase from Bacteroides thetaiotaomicron (BtOGA), a member of glycoside hydrolase family 84 (GH84), alongside an N-acetyl-D-glucosamine oxazoline derivative (GlcNAc-oxa) as the glycosyl donor. Furthermore, an investigation into glycosyl acceptor recognition in BtOGA-catalyzed enzymatic glycosylation indicated that the presence of an aromatic group at the anomeric position and an axial hydroxy group at the 4-position of the saccharide moiety is crucial for effective recognition of BtOGA as a glycosyl acceptor. The protecting-group-free chemoenzymatic synthesis of the core 6 disaccharide moiety was achieved by integrating the direct synthesis of GlcNAc-oxa thorough Shoda activation method using a water-soluble dehydration condensing agent in an aqueous medium, followed by BtOGA-catalyzed enzymatic glycosylation.
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Affiliation(s)
- Rika Okuno
- Department of Biobased Materials Science, Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Shunsuke Nakada
- Department of Biobased Materials Science, Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Kisuke Tonomura
- Department of Advanced Bioscience, Kindai University, Nakamachi, Nara, 631-8505, Japan
| | - Yuji Aso
- Department of Biobased Materials Science, Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Daijiro Takeshita
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan
| | - Takayuki Ohnuma
- Department of Advanced Bioscience, Kindai University, Nakamachi, Nara, 631-8505, Japan
- Agricultural Technology and Innovation Research Institute (ATIRI), Kindai University, Nakamachi, Nara, 631-8505, Japan
| | - Tomonari Tanaka
- Department of Biobased Materials Science, Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
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Jiang J, Luo Z, Zhang RC, Wang YL, Zhang J, Duan MY, Qiu ZJ, Huang C. Insights into the history and tendency of glycosylation and digestive system tumor: A bibliometric-based visual analysis. World J Gastrointest Oncol 2024; 16:1059-1075. [PMID: 38577469 PMCID: PMC10989360 DOI: 10.4251/wjgo.v16.i3.1059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND Glycosylation, a commonly occurring post-translational modification, is highly expressed in several tumors, specifically in those of the digestive system, and plays a role in various cellular pathophysiological mechanisms. Although the importance and detection methods of glycosylation in digestive system tumors have garnered increasing attention in recent years, bibliometric analysis of this field remains scarce. The present study aims to identify the developmental trends and research hotspots of glycosylation in digestive system tumors. AIM To find and identify the developmental trends and research hotspots of glycosylation in digestive system tumors. METHODS We obtained relevant literature from the Web of Science Core Collection and employed VOSviewer 1.6.19 and CiteSpace (version 6.1.R6) to perform bibliometric analysis. RESULTS A total of 2042 documents spanning from 1978 to the present were analyzed, with the research process divided into three phases: the period of obscurity (1978-1990), continuous development period (1991-2006), and the rapid outbreak period (2007-2023). These documents were authored by researchers from 66 countries or regions, with the United States and China leading in terms of publication output. Reis Celso A had the highest number of publications, while Pinho SS was the most cited author. Co-occurrence analysis revealed the most popular keywords in this field are glycosylation, expression, cancer, colorectal cancer, and pancreatic cancer. Furthermore, the Journal of Proteome Research was the most prolific journal in terms of publications, while the Journal of Biological Chemistry had the most citations. CONCLUSION The bibliometric analysis shows current research focus is primarily on basic research in this field. However, future research should aim to utilize glycosylation as a target for treating tumor patients.
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Affiliation(s)
- Jie Jiang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zai Luo
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Ren-Chao Zhang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yue-Ling Wang
- Jiangnan University Wuxi School of Medicine, Wuxi 214122, Jiangsu Province, China
| | - Jun Zhang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Ming-Yu Duan
- Department of Education, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zheng-Jun Qiu
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Chen Huang
- Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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Villarreal AR, Lucas SK, Fletcher JR, Hunter RC. High-throughput quantification of microbial-derived organic acids in mucin-rich samples via reverse phase high performance liquid chromatography. J Med Microbiol 2023; 72. [PMID: 37294285 DOI: 10.1099/jmm.0.001708] [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] [Indexed: 06/10/2023] Open
Abstract
Organic acids (short chain fatty acids, amino acids, etc.) are common metabolic byproducts of commensal bacteria of the gut and oral cavity in addition to microbiota associated with chronic infections of the airways, skin, and soft tissues. A ubiquitous characteristic of these body sites in which mucus-rich secretions often accumulate in excess, is the presence of mucins; high molecular weight (HMW), glycosylated proteins that decorate the surfaces of non-keratinized epithelia. Owing to their size, mucins complicate quantification of microbial-derived metabolites as these large glycoproteins preclude use of 1D and 2D gel approaches and can obstruct analytical chromatography columns. Standard approaches for quantification of organic acids in mucin-rich samples typically rely on laborious extractions or outsourcing to laboratories specializing in targeted metabolomics. Here we report a high-throughput sample preparation process that reduces mucin abundance and an accompanying isocratic reverse phase high performance liquid chromatography (HPLC) method that enables quantification of microbial-derived organic acids. This approach allows for accurate quantification of compounds of interest (0.01 mM - 100 mM) with minimal sample preparation, a moderate HPLC method run time, and preservation of both guard and analytical column integrity. This approach paves the way for further analyses of microbial-derived metabolites in complex clinical samples.
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Affiliation(s)
- Alex R Villarreal
- Department of Microbiology & Immunology, University of Minnesota, 689 23rd Avenue SE, Minneapolis, MN 55455, USA
| | - Sarah K Lucas
- Department of Microbiology & Immunology, University of Minnesota, 689 23rd Avenue SE, Minneapolis, MN 55455, USA
| | - Joshua R Fletcher
- Department of Microbiology & Immunology, University of Minnesota, 689 23rd Avenue SE, Minneapolis, MN 55455, USA
| | - Ryan C Hunter
- Department of Microbiology & Immunology, University of Minnesota, 689 23rd Avenue SE, Minneapolis, MN 55455, USA
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Gautam SK, Khan P, Natarajan G, Atri P, Aithal A, Ganti AK, Batra SK, Nasser MW, Jain M. Mucins as Potential Biomarkers for Early Detection of Cancer. Cancers (Basel) 2023; 15:1640. [PMID: 36980526 PMCID: PMC10046558 DOI: 10.3390/cancers15061640] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/10/2023] Open
Abstract
Early detection significantly correlates with improved survival in cancer patients. So far, a limited number of biomarkers have been validated to diagnose cancers at an early stage. Considering the leading cancer types that contribute to more than 50% of deaths in the USA, we discuss the ongoing endeavors toward early detection of lung, breast, ovarian, colon, prostate, liver, and pancreatic cancers to highlight the significance of mucin glycoproteins in cancer diagnosis. As mucin deregulation is one of the earliest events in most epithelial malignancies following oncogenic transformation, these high-molecular-weight glycoproteins are considered potential candidates for biomarker development. The diagnostic potential of mucins is mainly attributed to their deregulated expression, altered glycosylation, splicing, and ability to induce autoantibodies. Secretory and shed mucins are commonly detected in patients' sera, body fluids, and tumor biopsies. For instance, CA125, also called MUC16, is one of the biomarkers implemented for the diagnosis of ovarian cancer and is currently being investigated for other malignancies. Similarly, MUC5AC, a secretory mucin, is a potential biomarker for pancreatic cancer. Moreover, anti-mucin autoantibodies and mucin-packaged exosomes have opened new avenues of biomarker development for early cancer diagnosis. In this review, we discuss the diagnostic potential of mucins in epithelial cancers and provide evidence and a rationale for developing a mucin-based biomarker panel for early cancer detection.
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Affiliation(s)
- Shailendra K. Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Gopalakrishnan Natarajan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Apar K. Ganti
- Fred & Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Oncology-Hematology, Department of Internal Medicine, VA Nebraska Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Mohd W. Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Dkhil MA, Thagfan FA, Morad MY, Al-Shaebi EM, Elshanat S, Bauomy AA, Mubaraki M, Hafiz TA, Al-Quraishy S, Abdel-Gaber R. Biosynthesized silver nanoparticles have anticoccidial and jejunum-protective effects in mice infected with Eimeria papillata. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:44566-44577. [PMID: 36694067 PMCID: PMC9873539 DOI: 10.1007/s11356-023-25383-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 01/13/2023] [Indexed: 06/01/2023]
Abstract
Eimeriosis, an infection with Eimeria spp. that affects poultry, causes huge economic losses. Silver nanoparticles (AgNPs) have antibacterial and antifungal properties, but their action against Eimeria infection has not yet been elucidated. This study demonstrates the action of AgNPs in the treatment of mice infected with Eimeria papillata. AgNPs were prepared from Zingiber officinale rhizomes. Phytochemical screening by gas chromatography-mass spectrometry analysis (GC-MS) was used to detect active compounds. Mice were divided into five groups: uninfected mice, uninfected mice that were administered AgNPs, untreated mice infected with 103 sporulated oocysts of E. papillata, infected mice treated with AgNPs, and infected mice treated with amprolium. Characterization of the samples showed the AgNPs to have nanoscale sizes and aspherical shape. Phytochemical screening by GC-MS demonstrated the presence of 38 phytochemical compounds in the extract of Z. officinale. Mice infected with E. papillata-sporulated oocysts were observed to have many histopathological damages in the jejuna, including a decrease in the goblet cell numbers affecting the jejunal mucosa. Additionally, an increased oocyst output was also observed. The treatment of infected mice with AgNPs resulted in the improvement of the jejunal mucosa, increase in the number of goblet cell, and decrease in the number of meronts, gamonts, and developing oocysts in the jejuna. Moreover, AgNPs also led to decreased oocyst shedding in feces. The results revealed AgNPs to have an anticoccidial effect in the jejunum of E. papillata-infected mice and, thus, could be a potential treatment for eimeriosis.
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Affiliation(s)
- Mohamed A Dkhil
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
- Applied Science Research Center, Applied Science Private University, Amman, Jordan
| | - Felwa A Thagfan
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
| | - Mostafa Y Morad
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Esam M Al-Shaebi
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sherif Elshanat
- Department of Parasitology, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt
| | - Amira A Bauomy
- Department of Science Laboratories, College of Science and Arts, Qassim University, Ar-Rass, 52719, Saudi Arabia
| | - Murad Mubaraki
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Taghreed A Hafiz
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Saleh Al-Quraishy
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Rewaida Abdel-Gaber
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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Proteomic Analysis Reveals Molecular Differences in the Development of Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:8266544. [PMID: 35958927 PMCID: PMC9357686 DOI: 10.1155/2022/8266544] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/18/2022] [Accepted: 06/23/2022] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is the 3rd leading cause of death from cancer and the 5th most common cancer worldwide. The detection rate of GC among Tibetans is significantly higher than that in Han Chinese, probably due to differences in their living habits, dietary structure, and environment. Despite such a high disease burden, the epidemiology of gastric cancer has not been studied in this population. Molecular markers are required to aid the diagnosis and treatment of GC. In this study, we collected gastric tissue samples from patients in Tibet with chronic nonatrophic gastritis (CNAG) (n = 6), chronic atrophic gastritis (CAG) (n = 7), gastric intraepithelial neoplasia (GIN) (n = 4), and GC (n = 5). The proteins in each group were analyzed using coupled label-free mass spectrometry. In addition, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein interaction networks were used to analyze the differentially expressed proteins (DEPs) among groups. DEPs were quantified in comparisons of GC versus CNAG (223), GC versus GIN (100), and GIN versus CNAG (341). GO and KEGG analyses showed that the DEPs were mainly associated with immunity (GC versus CNAG) and cancer proliferation and metastasis (GC versus GIN, and GIN versus CNAG). Furthermore, the expression levels of cell proliferation and cytoskeleton-related proteins increased consistently during cancer development, such as ITGA4, DDC, and CPT1A; thus, they are potential diagnostic markers. These results obtained by proteomics analysis could improve our understanding of cancer biology in GC and provide a rich resource for data mining and discovering potential immunotherapy targets.
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Wakao M, Miyahara T, Iiboshi K, Hashiguchi N, Masunaga N, Suda Y. Synthesis of mucin type core 3 and core 5 structures and their interaction analysis with sugar chips. Carbohydr Res 2022; 516:108565. [DOI: 10.1016/j.carres.2022.108565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/15/2022] [Accepted: 04/19/2022] [Indexed: 11/02/2022]
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Yuki A, Fujii C, Yamanoi K, Matoba H, Harumiya S, Kawakubo M, Nakayama J. Glycosylation of MUC6 by α1,4-linked N-acetylglucosamine enhances suppression of pancreatic cancer malignancy. Cancer Sci 2021; 113:576-586. [PMID: 34808019 PMCID: PMC8819301 DOI: 10.1111/cas.15209] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 11/27/2022] Open
Abstract
Biomarkers for early diagnosis of pancreatic cancer are greatly needed, as the high fatality of this cancer is in part due to delayed detection. α1,4‐linked N‐acetylglucosamine (αGlcNAc), a unique O‐glycan specific to gastric gland mucus, is biosynthesized by α1,4‐N‐acetylglucosaminyltransferase (α4GnT) and primarily bound at the terminal glycosylated residue to scaffold protein MUC6. We previously reported that αGlcNAc expression decreases at early stages of neoplastic pancreatic lesions, followed by decreased MUC6 expression, although functional effects of these outcomes were unknown. Here, we ectopically expressed α4GnT, the αGlcNAc biosynthetic enzyme, together with MUC6 in the human pancreatic cancer cell lines MIA PaCa‐2 and PANC‐1, neither of which expresses α4GnT and MUC6. We observed significantly suppressed proliferation in both lines following coexpression of α4GnT and MUC6. Moreover, cellular motility decreased following MUC6 ectopic expression, an effect enhanced by cotransduction with α4GnT. MUC6 expression also attenuated invasiveness of both lines relative to controls, and this effect was also enhanced by additional α4GnT expression. We found αGlcNAc‐bound MUC6 formed a complex with trefoil factor 2. Furthermore, analysis of survival curves of patients with pancreatic ductal adenocarcinoma using a gene expression database showed that samples marked by higher A4GNT or MUC6 mRNA levels were associated with relatively favorable prognosis. These results strongly suggest that αGlcNAc and MUC6 function as tumor suppressors in pancreatic cancer and that decreased expression of both may serve as a biomarker of tumor progression to pancreatic cancer.
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Affiliation(s)
- Atsuko Yuki
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Chifumi Fujii
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.,Department of Biotechnology, Interdisciplinary Cluster for Cutting Edge Research, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
| | - Kazuhiro Yamanoi
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.,Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hisanori Matoba
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Harumiya
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masatomo Kawakubo
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Jun Nakayama
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
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Oral O, Unverdi H, Kumcu E, Turkbey D, Dogan S, Hucumenoglu S. Associations between the expression of mucins (MUC1, MUC2, MUC5AC and MUC6) and clinicopathologic parameters of human breast carcinomas. INDIAN J PATHOL MICR 2021; 63:551-558. [PMID: 33154304 DOI: 10.4103/ijpm.ijpm_637_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Aims The aim of this study is to evaluate the relationships between the expression of mucins in invasive breast carcinomas and clinicopathologic parameters. Materials and Methods We examined 150 cases of invasive breast carcinoma, using the 2012 World Health Organization (WHO) classification of the tumors of the breast. We studied the expression of MUC1, MUC2, MUC5AC, and MUC6 by immunohistochemistry. We also evaluated normal breast tissue and ductal carcinoma in situ (DCIS) lesions in nearby invasive tumor areas. Results In invasive breast carcinomas, MUC1, MUC2, MUC5AC, and MUC6 were expressed in 98.6%, 11.3%, 9.9, and 8.5% of cases, respectively. MUC2, MUC5AC, and MUC6 were overexpressed in invasive tumors and DCIS lesions were compared with normal breast tissue. The apical pattern of MUC1 was correlated with low grade and ER expression. MUC2 was correlated with mucinous carcinoma and an inverse association with invasive ductal carcinoma, not otherwise specified (NOS). MUC6 expression was associated with lymphovascular invasion. Conclusions Most invasive breast tumors express MUC1 and the apical pattern of MUC1 is correlated with low grade and ER expression. MUC6 expression is associated with indicators of poor prognosis. Further comprehensive studies need to evaluate the role of mucins as a potential biomarker and to be used as a specific therapeutic target against breast cancer.
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Affiliation(s)
- Onur Oral
- Department of Pathology, Manavgat State Hospital, Antalya, Turkey
| | - Hatice Unverdi
- Department of Pathology, Ankara Education and Research Hospital, Ankara, Turkey
| | - Emrah Kumcu
- Department of Pathology, Bingol State Hospital, Bingol, Turkey
| | - Duygu Turkbey
- Department of Pathology, Baskent University, Ankara, Turkey
| | - Serdar Dogan
- Department of Biochemistry, Mustafa Kemal University, Hatay, Turkey
| | - Sema Hucumenoglu
- Department of Pathology, Ankara Education and Research Hospital, Ankara, Turkey
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Battista S, Ambrosio MR, Limarzi F, Gallo G, Saragoni L. Molecular Alterations in Gastric Preneoplastic Lesions and Early Gastric Cancer. Int J Mol Sci 2021; 22:6652. [PMID: 34206291 PMCID: PMC8268370 DOI: 10.3390/ijms22136652] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/16/2022] Open
Abstract
Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.
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Affiliation(s)
- Serena Battista
- Pathology Department, “S. Maria della Misericordia Hospital”, Friuli-Venezia Giulia, 33100 Udine, Italy
| | | | - Francesco Limarzi
- Pathology Department, “G.B. Morgagni-L. Pierantoni Hospital”, Emilia-Romagna, 47121 Forlì, Italy; (F.L.); (L.S.)
| | - Graziana Gallo
- Pathology Department, “M. Bufalini Hospital”, Emilia Romagna, 47521 Cesena, Italy;
| | - Luca Saragoni
- Pathology Department, “G.B. Morgagni-L. Pierantoni Hospital”, Emilia-Romagna, 47121 Forlì, Italy; (F.L.); (L.S.)
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Wu MY, Hou YT, Ke JY, Yiang GT. Case of internal jugular vein thrombosis and fever: Lemierre's syndrome or Trousseau's syndrome? Tzu Chi Med J 2020; 32:91-95. [PMID: 32110528 PMCID: PMC7015004 DOI: 10.4103/tcmj.tcmj_34_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 01/12/2019] [Accepted: 02/01/2019] [Indexed: 12/21/2022] Open
Abstract
Internal jugular vein thrombosis is a rare critical cardiovascular emergency, which has potential catastrophic clinical outcomes by resulting in stroke and pulmonary embolism. Several etiologies have been reported; however, there are limited data on Lemierre's and Trousseau's syndromes, which are both rare conditions with advanced disease progression and poor clinical outcomes. Lemierre's syndrome may present with typical progressively infectious symptoms and signs, including sore throat, neck mass, and fever, whereas Trousseau's syndrome may present with thrombophlebitis and painful edema. Without antibiotic agents controlling the infection, the condition of patients with Lemierre's syndrome may progress to sepsis or septic shock. The infection pattern plays an important role for differential diagnosis. Herein, we describe the case of a 46-year-old woman presenting with atypical symptoms of Trousseau's syndrome mimicking Lemierre's syndrome. Laboratory analysis including protein C, protein S, rheumatoid factor, and antinuclear antibody ruled out hypercoagulopathy and autoimmune vasculitis. Abdominal computed tomography and panendoscopy revealed ulcerative tumor at the antrum. Pathological examination confirmed the presence of signet-ring cell adenocarcinoma. We highlight the clinical features and etiologies of internal jugular vein thrombosis, especially in Lemierre's syndrome and Trousseau's syndrome, to aid physicians in making an early diagnosis and providing timely management.
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Affiliation(s)
- Meng-Yu Wu
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Yueh-Tseng Hou
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Jian-Yu Ke
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Giou-Teng Yiang
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan
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Mao Y, Zhang Y, Fan S, Chen L, Tang L, Chen X, Lyu J. GALNT6 Promotes Tumorigenicity and Metastasis of Breast Cancer Cell via β-catenin/MUC1-C Signaling Pathway. Int J Biol Sci 2019; 15:169-182. [PMID: 30662357 PMCID: PMC6329923 DOI: 10.7150/ijbs.29048] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 11/02/2018] [Indexed: 01/07/2023] Open
Abstract
Polypeptide N-acetylgalactosaminyl transferase-6 (GALNT6), a member of the N-acetyl-D-galactosamine transferase family, was shown to be over-expression in mammary cancer and could be used as a biomarker. However, its roles and underlying mechanisms in the pathogenesis of breast cancer are still unclear. In this study, we reported that GALNT6 was up-expression in breast cancer, and it was not associated with tumor stage. The expression level of GALNT6 and menopause status was associated with patient survival. Biological function results illustrated that knockdown of GALNT6 inhibited proliferation, migration and invasion of MDA-MB-231 cells, and increased cell apoptosis. Knockdown of GALNT6 in breast cancer cell attenuated the protein expression of PCNA, cyclin D1, C-myc and β-catenin, and increased the expression of E-cadherin, caspase 3 and cleaved PARP1. Cell fractionation assay showed that knockdown of GALNT6 reduced the levels of β-catenin and MUC1-C in nucleus. Simultaneously knockdown of GALNT6 and β-catenin significantly reduced the level of C-myc. Co-IP experiments indicated that GALNT6 interacted with MUC1-N, β-catenin interacting with MUC1-C in breast cancer cells. Together, our study reveals that GALNT6 promotes tumorigenicity and metastasis through β-catenin/MUC1-C signaling pathway.
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Affiliation(s)
- Yingge Mao
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Present address: The First Affiliated Hospital of Henan University
| | - Yuqi Zhang
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Sairong Fan
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lvao Chen
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lili Tang
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaoming Chen
- Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianxin Lyu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Hangzhou Medical College, Hangzhou, Zhejiang, China
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Abstract
Heparin and heparan sulfate (HS) are polydisperse mixtures of polysaccharide chains between 5 and 50 kDa. Sulfate modifications to discreet regions along the chains form protein binding sites involved in cell signaling cascades and other important cellular physiological and pathophysiological functions. Specific protein affinities of the chains vary among different tissues and are determined by the arrangements of sulfated residues in discreet regions along the chains which in turn appear to be determined by the expression levels of particular enzymes in the biosynthetic pathway. Although not all the rules governing synthesis and modification are known, analytical procedures have been developed to determine composition, and all of the biosynthetic enzymes have been identified and cloned. Thus, through cell engineering, it is now possible to direct cellular synthesis of heparin and HS to particular compositions and therefore particular functional characteristics. For example, directing heparin producing cells to reduce the level of a particular type of polysaccharide modification may reduce the risk of heparin induced thrombocytopenia (HIT) without reducing the potency of anticoagulation. Similarly, HS has been linked to several biological areas including wound healing, cancer and lipid metabolism among others. Presumably, these roles involve specific HS compositions that could be produced by engineering cells. Providing HS reagents with a range of identified compositions should help accelerate this research and lead to new clinical applications for specific HS compositions. Here I review progress in engineering CHO cells to produce heparin and HS with compositions directed to improved properties and advancing medical research.
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Alkhudhayri AA, Dkhil MA, Al-Quraishy S. Nanoselenium prevents eimeriosis-induced inflammation and regulates mucin gene expression in mice jejunum. Int J Nanomedicine 2018; 13:1993-2003. [PMID: 29662312 PMCID: PMC5892949 DOI: 10.2147/ijn.s162355] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background Although elemental selenium has been found to be effective against Eimeria, no study has yet investigated the effects of selenium nanoparticles (SeNPs) on the Eimeria parasite. The aim of this study, therefore, was to evaluate the ameliorative effect of SeNPs compared with elemental selenium on mice jejunum infected with sporulated oocysts of Eimeria papillata. Methods The mice were divided into 4 groups, with the first being the non-infected, control group, and the second, third, and fourth groups being orally inoculated with 1,000 sporulated oocysts of E. papillata. The third and fourth groups also received, respectively, an oral dose of 0.1 mg/kg sodium selenite and 0.5 mg/kg SeNPs daily for 5 consecutive days. Results The infection induced severe histopathological jejunal damage, reflected in the form of destroyed jejunal mucosa, increased jejunal oxidative damage, a reduction in the number of jejunal goblet cells, and increased production of pro-inflammatory cytokines, quantified by real-time polymerase chain reaction. Treatment of mice with SeNPs significantly decreased the oocyst output in the feces by ~80%. Furthermore, the number of parasitic stages counted in stained jejunal paraffin sections was significantly decreased after the mice were treated with SeNPs. In addition, the number of goblet cells increased from 42.6±7.3 to 95.3±8.5 cells/10 villus-crypt units after treatment. By day 5 post-infection with E. papillata, SeNPs could be seen to have significantly increased the activity of glutathione peroxidase from 263±10 to 402.4±9 mU/mL. Finally, SeNPs were able to regulate the gene expression of mucin 2, interleukin 1β, interleukin 6, interferon-γ, and tumor necrosis factor α in the jejunum of mice infected with E. papillata. Conclusion The results collectively showed that SeNPs are more effective than sodium selenite with regard to their anti-coccidial, anti-oxidant, and anti-inflammatory role against eimeriosis induced in the jejunum of mice.
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Affiliation(s)
| | - Mohamed A Dkhil
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.,Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Saleh Al-Quraishy
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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Takeda N, Takei T, Asahina Y, Hojo H. Sialyl Tn Unit with TFA‐Labile Protection Realizes Efficient Synthesis of Sialyl Glycoprotein. Chemistry 2018; 24:2593-2597. [DOI: 10.1002/chem.201706127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Indexed: 11/09/2022]
Affiliation(s)
- Naoki Takeda
- Institute for Protein Research Osaka University Osaka 565-0871 Japan
| | - Toshiki Takei
- Institute for Protein Research Osaka University Osaka 565-0871 Japan
| | - Yuya Asahina
- Institute for Protein Research Osaka University Osaka 565-0871 Japan
| | - Hironobu Hojo
- Institute for Protein Research Osaka University Osaka 565-0871 Japan
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Dhanisha SS, Guruvayoorappan C, Drishya S, Abeesh P. Mucins: Structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets. Crit Rev Oncol Hematol 2017; 122:98-122. [PMID: 29458795 DOI: 10.1016/j.critrevonc.2017.12.006] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 10/28/2017] [Accepted: 12/12/2017] [Indexed: 12/25/2022] Open
Abstract
Mucins are the main structural components of mucus that create a selective protective barrier for epithelial surface and also execute wide range of other physiological functions. Mucins can be classified into two types, namely secreted mucins and membrane bounded mucins. Alterations in mucin expression or glycosylation and mislocalization have been seen in various types of pathological conditions such as cancers, inflammatory bowel disease and ocular disease, which highlight the importance of mucin in maintaining homeostasis. Hence mucins can be used as attractive target for therapeutic intervention. In this review, we discuss in detail about the structural diversity of mucins; their biosynthesis; its role in pathogenesis; regulation and as possible therapeutic targets.
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Affiliation(s)
- Suresh Sulekha Dhanisha
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Chandrasekharan Guruvayoorappan
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India.
| | - Sudarsanan Drishya
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Prathapan Abeesh
- Laboratory of Immunopharmacology and Experimental Therapeutics, Division of Cancer Research, Regional Cancer Centre, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
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Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma. Int J Oncol 2017; 52:139-154. [PMID: 29138803 PMCID: PMC5743405 DOI: 10.3892/ijo.2017.4199] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 10/27/2017] [Indexed: 02/06/2023] Open
Abstract
Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR-302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP-1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand-receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function.
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The cell surface mucin MUC1 limits the severity of influenza A virus infection. Mucosal Immunol 2017; 10:1581-1593. [PMID: 28327617 DOI: 10.1038/mi.2017.16] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/26/2017] [Indexed: 02/04/2023]
Abstract
Cell surface mucin (cs-mucin) glycoproteins are constitutively expressed at the surface of respiratory epithelia where pathogens such as influenza A virus (IAV) gain entry into cells. Different members of the cs-mucin family each express a large and heavily glycosylated extracellular domain that towers above other receptors on the epithelial cell surface, a transmembrane domain that enables shedding of the extracellular domain, and a cytoplasmic tail capable of triggering signaling cascades. We hypothesized that IAV can interact with the terminal sialic acids presented on the extracellular domain of cs-mucins, resulting in modulation of infection efficiency. Utilizing human lung epithelial cells, we found that IAV associates with the cs-mucin MUC1 but not MUC13 or MUC16. Overexpression of MUC1 by epithelial cells or the addition of sialylated synthetic MUC1 constructs, reduced IAV infection in vitro. In addition, Muc1-/- mice infected with IAV exhibited enhanced morbidity and mortality, as well as greater inflammatory mediator responses compared to wild type mice. This study implicates the cs-mucin MUC1 as a critical and dynamic component of the innate host response that limits the severity of influenza and provides the foundation for exploration of MUC1 in resolving inflammatory disease.
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19
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Xu T, Li D, Wang H, Zheng T, Wang G, Xin Y. MUC1 downregulation inhibits non-small cell lung cancer progression in human cell lines. Exp Ther Med 2017; 14:4443-4447. [PMID: 29104655 DOI: 10.3892/etm.2017.5062] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 05/19/2017] [Indexed: 12/29/2022] Open
Abstract
Mucin 1 (MUC1) is a transmembrane glycoprotein that is aberrantly unregulated in numerous types of cancer, including non-small cell lung cancer (NSCLC), and serves a key role as an oncogene in the tumorigenesis of various human adenocarcinomas. Studies have indicated that MUC1 is involved in cell proliferation, invasion and migration. However, the role of MUC1 in NSCLC progression remains poorly understood. The aim of the present study was to investigate the role of MUC1 in stable MUC1-low-expression NSCLC cell lines that were generated by transfection with MUC1-siRNA. Cell Counting Kit-8 assay was preformed to determine the proliferation ability of NSCLC cells, while cell apoptosis was detected using flow cytometry. In addition, the mRNA and protein expression levels of MUC1 were detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Western blot analysis was also used for detection of other associated proteins. The results demonstrated that, compared with the control group, the cell proliferation ability was significantly declined in the MUC1 inhibition group, and the cell apoptosis rate was markedly increased. Inhibition of MUC1 gene in NCI-H1650 cells suppressed cell proliferation and induced cell apoptosis. In addition, the protein expression levels of vascular endothelial growth factor (VEGF) and VEGF-C were notably decreased by MUC1 inhibition, indicating the anti-angiogenic effect of MUC1 downregulation. Furthermore, inhibition of MUC1 gene with MUC1-siRNA significantly suppressed the phosphorylation of protein kinase B and extracellular signal-regulated kinase. In conclusion, the findings indicated that silencing of MUC1 gene may inhibit the development of NSCLC cells.
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Affiliation(s)
- Tao Xu
- Department of Respiratory Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Daowei Li
- Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Hongmei Wang
- Department of Respiratory Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Taohua Zheng
- Department of Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Guangqiang Wang
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ying Xin
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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20
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Tavernaro I, Hartmann S, Sommer L, Hausmann H, Rohner C, Ruehl M, Hoffmann-Roeder A, Schlecht S. Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids. Org Biomol Chem 2015; 13:81-97. [PMID: 25212389 DOI: 10.1039/c4ob01339e] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The mucin MUC1 is a glycoprotein involved in fundamental biological processes, which can be found over-expressed and with a distinctly altered glycan pattern on epithelial tumor cells; thus it is a promising target structure in the quest for effective carbohydrate-based cancer vaccines and immunotherapeutics. Natural glycopeptide antigens indicate only a low immunogenicity and a T-cell independent immune response; however, this major drawback can be overcome by coupling of glycopeptide antigens multivalently to immunostimulating carrier platforms. In particular, gold nanoparticles are well suited as templates for the multivalent presentation of glycopeptide antigens, due to their remarkably high surface-to-volume ratio in combination with their high biostability. In this work the synthesis of novel MUC1-glycopeptide antigens and their coupling to gold nanoparticles of different sizes are presented. In addition, the development of a new dot-blot immunoassay to test the potential antigen-antibody binding is introduced.
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Affiliation(s)
- Isabella Tavernaro
- Institute of Inorganic and Analytical Chemistry, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany.
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Vitiazeva V, Kattla JJ, Flowers SA, Lindén SK, Premaratne P, Weijdegård B, Sundfeldt K, Karlsson NG. The O-Linked Glycome and Blood Group Antigens ABO on Mucin-Type Glycoproteins in Mucinous and Serous Epithelial Ovarian Tumors. PLoS One 2015; 10:e0130197. [PMID: 26075384 PMCID: PMC4468167 DOI: 10.1371/journal.pone.0130197] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 05/16/2015] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Mucins are heavily O-glycosylated proteins where the glycosylation has been shown to play an important role in cancer. Normal epithelial ovarian cells do not express secreted mucins, but their abnormal expression has previously been described in epithelial ovarian cancer and may relate to tumor formation and progression. The cyst fluids were shown to be a rich source for acidic glycoproteins. The study of these proteins can potentially lead to the identification of more effective biomarkers for ovarian cancer. METHODS In this study, we analyzed the expression of the MUC5AC and the O-glycosylation of acidic glycoproteins secreted into ovarian cyst fluids. The samples were obtained from patients with serous and mucinous ovarian tumors of different stages (benign, borderline, malignant) and grades. The O-linked oligosaccharides were released and analyzed by negative-ion graphitized carbon Liquid Chromatography (LC) coupled to Electrospray Ionization tandem Mass Spectrometry (ESI-MSn). The LC-ESI-MSn of the oligosaccharides from ovarian cyst fluids displayed differences in expression of fucose containing structures such as blood group ABO antigens and Lewis-type epitopes. RESULTS The obtained data showed that serous and mucinous benign adenomas, mucinous low malignant potential carcinomas (LMPs, borderline) and mucinous low-grade carcinomas have a high level of blood groups and Lewis type epitopes. In contrast, this type of fucosylated structures were low abundant in the high-grade mucinous carcinomas or in serous carcinomas. In addition, the ovarian tumors that showed a high level of expression of blood group antigens also revealed a strong reactivity towards the MUC5AC antibody. To visualize the differences between serous and mucinous ovarian tumors based on the O-glycosylation, a hierarchical cluster analysis was performed using mass spectrometry average compositions (MSAC). CONCLUSION Mucinous benign and LMPs along with mucinous low-grade carcinomas appear to be different from serous and high-grade mucinous carcinomas based on their O-glycan profiles.
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Affiliation(s)
- Varvara Vitiazeva
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
- * E-mail:
| | - Jayesh J. Kattla
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Sarah A. Flowers
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Sara K. Lindén
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Pushpa Premaratne
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Birgitta Weijdegård
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | - Karin Sundfeldt
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | - Niclas G. Karlsson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
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Demian WLL, Kottari N, Shiao TC, Randell E, Roy R, Banoub JH. Direct targeted glycation of the free sulfhydryl group of cysteine residue (Cys-34) of BSA. Mapping of the glycation sites of the anti-tumor Thomsen-Friedenreich neoglycoconjugate vaccine prepared by Michael addition reaction. JOURNAL OF MASS SPECTROMETRY : JMS 2014; 49:1223-1233. [PMID: 25476939 DOI: 10.1002/jms.3448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 07/22/2014] [Indexed: 06/04/2023]
Abstract
We present in this manuscript the characterization of the exact glycation sites of the Thomsen-Friedenreich antigen-BSA vaccine (TF antigen:BSA) prepared using a Michael addition reaction between the saccharide antigen as an electrophilic acceptor and the nucleophilic thiol and L-Lysine ε-amino groups of BSA using different ligation conditions. Matrix laser desorption ionization time-of-flight mass spectrometry of the neoglycoconjugates prepared with TF antigen:protein ratios of 2:1 and 8:1, allowed to observe, respectively, the protonated molecules for each neoglycoconjugates: [M + H](+) at m/z 67,599 and 70,905. The measurements of these molecular weights allowed us to confirm exactly the carbohydrate:protein ratios of these two synthetic vaccines. These were found to be closely formed by a TF antigen:BSA ratios of 2:1 and 8:1, respectively. Trypsin digestion and liquid chromatography coupled with electrospray ionization mass spectrometry allowed us to identify the series of released glycopeptide and peptide fragments. De novo sequencing affected by low-energy collision dissociation tandem mass spectrometry was then employed to unravel the precise glycation sites of these neoglycoconjugate vaccines. Finally, we identified, respectively, three diagnostic and characteristic glycated peptides for the synthetic glycoconjugate possessing a TF antigen:BSA ratio 2:1, whereas we have identified for the synthetic glycoconjugate having a TF:BSA ratio 8:1 a series of 14 glycated peptides. The net increase in the occupancy sites of these neoglycoconjugates was caused by the large number of glycoforms produced during the chemical ligation of the synthetic carbohydrate antigen onto the protein carrier.
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Affiliation(s)
- Wael L L Demian
- Department of Biochemistry, Memorial University of Newfoundland, St. John's Newfoundland, A1B 3X9, Canada
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Mego M, Zuo Z, Gao H, Cohen EN, Giordano A, Tin S, Anfossi S, Jackson S, Woodward W, Ueno NT, Valero V, Alvarez RH, Hortobagyi GN, Khoury JD, Cristofanilli M, Reuben JM. Circulating tumour cells are linked to plasma D-dimer levels in patients with metastatic breast cancer. Thromb Haemost 2014; 113:593-8. [PMID: 25373787 DOI: 10.1160/th14-07-0597] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 09/15/2014] [Indexed: 01/02/2023]
Abstract
Cancer is a risk factor for venous thromboembolism (VTE). Elevated plasma D-dimer and fibrinogen levels are also risk factors for VTE. Furthermore, in patients with metastatic breast cancer (MBC), the presence of circulating tumour cells (CTCs) is a risk factor for VTE. The relationship between CTCs and D-dimer is unknown. The aim of this study was to determine whether CTCs correlate with plasma D-dimer level, fibrinogen level, and risk of VTE in MBC. This prospective study included 47 MBC patients treated from July 2009 through December 2010 at the MD Anderson Cancer Center. CTCs in peripheral blood were detected and enumerated using the CellSearch system. D-dimer and fibrinogen were measured in plasma at the time of CTC detection. Thirty-three patients (70 %) had ≥ 1 CTC, and 22 patients (47 %) had ≥ 5 CTCs. Patients with ≥ 1 CTC or ≥ 5 CTCs had significantly higher mean plasma D-dimer levels (µg/mL) than patients with no CTCs and < 5 CTCs (2.48 and 3.31 vs 0.80 and 0.84, respectively; p=0.006 for cut-off ≥ 1 CTC and p=0.003 for cut-off ≥ 5 CTCs). In multivariate analysis, presence of CTCs and number of metastases were positively associated with plasma D-dimer level. CTCs were not associated with plasma fibrinogen level. At median follow-up of 13.5 months, three of 33 patients (9 %) with ≥ 1 CTC had VTE, vs no patients with undetectable CTCs. In conclusion, the presence of CTCs was associated with higher levels of plasma D-dimer in MBC patients. This study further confirms an association between CTCs and risk of VTE.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - James M Reuben
- Dr. J. M. Reuben, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA, Tel.: +1 713 745 6837, Fax: +1 713 794 1838, E-mail:
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Gomes AM, Kozlowski EO, Borsig L, Teixeira FCOB, Vlodavsky I, Pavão MSG. Antitumor properties of a new non-anticoagulant heparin analog from the mollusk Nodipecten nodosus: Effect on P-selectin, heparanase, metastasis and cellular recruitment. Glycobiology 2014; 25:386-93. [DOI: 10.1093/glycob/cwu119] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Rachel H, Chang-Chun L. Recent advances toward the development of inhibitors to attenuate tumor metastasis via the interruption of lectin-ligand interactions. Adv Carbohydr Chem Biochem 2014; 69:125-207. [PMID: 24274369 DOI: 10.1016/b978-0-12-408093-5.00005-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aberrant glycosylation is a well-recognized phenomenon that occurs on the surface of tumor cells, and the overexpression of a number of ligands (such as TF, sialyl Tn, and sialyl Lewis X) has been correlated to a worse prognosis for the patient. These unique carbohydrate structures play an integral role in cell-cell communication and have also been associated with more metastatic cancer phenotypes, which can result from binding to lectins present on cell surfaces. The most well studied metastasis-associated lectins are the galectins and selectins, which have been correlated to adhesion, neoangiogenesis, and immune-cell evasion processes. In order to slow the rate of metastatic lesion formation, a number of approaches have been successfully developed which involve interfering with the tumor lectin-substrate binding event. Through the generation of inhibitors, or by attenuating lectin and/or carbohydrate expression, promising results have been observed both in vitro and in vivo. This article briefly summarizes the involvement of lectins in the metastatic process and also describes different approaches used to prevent these undesirable carbohydrate-lectin binding events, which should ultimately lead to improvement in current cancer therapies.
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Affiliation(s)
- Hevey Rachel
- Alberta Glycomics Centre, Department of Chemistry, University of Calgary, Calgary, Alberta, Canada
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Barreto SG, Dutt A, Chaudhary A. A genetic model for gallbladder carcinogenesis and its dissemination. Ann Oncol 2014; 25:1086-1097. [PMID: 24705974 PMCID: PMC4037856 DOI: 10.1093/annonc/mdu006] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 11/05/2013] [Accepted: 11/08/2013] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer, although regarded as the most common malignancy of the biliary tract, continues to be associated with a dismal overall survival even in the present day. While complete surgical removal of the tumour offers a good chance of cure, only a fraction of the patients are amenable to curative surgery owing to their delayed presentation. Moreover, the current contribution of adjuvant therapies towards prolonging survival is marginal, at best. Thus, understanding the biology of the disease will not only enable a better appreciation of the pathways of progression but also facilitate the development of an accurate genetic model for gallbladder carcinogenesis and dissemination. This review provides an updated, evidence-based model of the pathways of carcinogenesis in gallbladder cancer and its dissemination. The model proposed could serve as the scaffolding for elucidation of the molecular mechanisms involved in gallbladder carcinogenesis. A better understanding of the pathways involved in gallbladder tumorigenesis will serve to identify patients at risk for the cancer (and who thus could be offered prophylactic cholecystectomy) as well as aid oncologists in planning the most suitable treatment for a particular patient, thereby setting us on the vanguard of transforming the current treatment paradigm for gallbladder cancer.
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Affiliation(s)
- S G Barreto
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon
| | - A Dutt
- The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India
| | - A Chaudhary
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon
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Maemura M, Ohgaki A, Nakahara Y, Hojo H, Nakahara Y. Solid-Phase Synthesis of Core 8O-Glycan-Linked MUC5AC Glycopeptide. Biosci Biotechnol Biochem 2014; 69:1575-83. [PMID: 16116288 DOI: 10.1271/bbb.69.1575] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The benzyl-protected disaccharide building blocks of core 8 O-glycan (15a/15b) for glycopeptide were stereoselectively synthesized by two glycosidation reactions with the glycosyl fluoride method. The building blocks were utilized in the solid-phase synthesis of a glycopeptide carrying two O-glycans with the consensus sequence of the tandem-repeat domain of MUC5AC. The synthetic glycopeptide was detached from the resin with reagent K, and subsequent debenzylation under conditions of low-acidity TfOH afforded glycopeptide 2. The synthetic sample will be used as a suitable standard in studies of the physicochemical or immunochemical characterization of mucin glycoforms.
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Affiliation(s)
- Makoto Maemura
- Department of Applied Biochemistry, Institute of Glycotechnology, Tokai University, Kanagawa, Japan
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Aberrant glycosylation as biomarker for cancer: focus on CD43. BIOMED RESEARCH INTERNATIONAL 2014; 2014:742831. [PMID: 24689054 PMCID: PMC3943294 DOI: 10.1155/2014/742831] [Citation(s) in RCA: 280] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/10/2013] [Indexed: 11/23/2022]
Abstract
Glycosylation is a posttranslational modification of proteins playing a major role in cell signalling, immune recognition, and cell-cell interaction because of their glycan branches conferring structure variability and binding specificity to lectin ligands. Aberrant expression of glycan structures as well as occurrence of truncated structures, precursors, or novel structures of glycan may affect ligand-receptor interactions and thus interfere with regulation of cell adhesion, migration, and proliferation. Indeed, aberrant glycosylation represents a hallmark of cancer, reflecting cancer-specific changes in glycan biosynthesis pathways such as the altered expression of glycosyltransferases and glycosidases. Most studies have been carried out to identify changes in serum glycan structures. In most cancers, fucosylation and sialylation are significantly modified. Thus, aberrations in glycan structures can be used as targets to improve existing serum cancer biomarkers. The ability to distinguish differences in the glycosylation of proteins between cancer and control patients emphasizes glycobiology as a promising field for potential biomarker identification. In this review, we discuss the aberrant protein glycosylation associated with human cancer and the identification of protein glycoforms as cancer biomarkers. In particular, we will focus on the aberrant CD43 glycosylation as cancer biomarker and the potential to exploit the UN1 monoclonal antibody (UN1 mAb) to identify aberrant CD43 glycoforms.
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Häuselmann I, Borsig L. Altered tumor-cell glycosylation promotes metastasis. Front Oncol 2014; 4:28. [PMID: 24592356 PMCID: PMC3923139 DOI: 10.3389/fonc.2014.00028] [Citation(s) in RCA: 280] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 01/29/2014] [Indexed: 12/14/2022] Open
Abstract
Malignant transformation of cells is associated with aberrant glycosylation presented on the cell-surface. Commonly observed changes in glycan structures during malignancy encompass aberrant expression and glycosylation of mucins; abnormal branching of N-glycans; and increased presence of sialic acid on proteins and glycolipids. Accumulating evidence supports the notion that the presence of certain glycan structures correlates with cancer progression by affecting tumor-cell invasiveness, ability to disseminate through the blood circulation and to metastasize in distant organs. During metastasis tumor-cell-derived glycans enable binding to cells in their microenvironment including endothelium and blood constituents through glycan-binding receptors – lectins. In this review, we will discuss current concepts how tumor-cell-derived glycans contribute to metastasis with the focus on three types of lectins: siglecs, galectins, and selectins. Siglecs are present on virtually all hematopoietic cells and usually negatively regulate immune responses. Galectins are mostly expressed by tumor cells and support tumor-cell survival. Selectins are vascular adhesion receptors that promote tumor-cell dissemination. All lectins facilitate interactions within the tumor microenvironment and thereby promote cancer progression. The identification of mechanisms how tumor glycans contribute to metastasis may help to improve diagnosis, prognosis, and aid to develop clinical strategies to prevent metastasis.
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Affiliation(s)
- Irina Häuselmann
- Zürich Center for Integrative Human Physiology, Institute of Physiology, University of Zürich , Zürich , Switzerland
| | - Lubor Borsig
- Zürich Center for Integrative Human Physiology, Institute of Physiology, University of Zürich , Zürich , Switzerland
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Glycoconjugate Vaccines Used for Prevention from Biological Agents: Tandem Mass Spectrometric Analysis. DETECTION OF CHEMICAL, BIOLOGICAL, RADIOLOGICAL AND NUCLEAR AGENTS FOR THE PREVENTION OF TERRORISM 2014. [DOI: 10.1007/978-94-017-9238-7_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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31
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Liu X, Yi C, Wen Y, Radhakrishnan P, Tremayne JR, Dao T, Johnson KR, Hollingsworth MA. Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis. Cancer Res 2013; 74:1609-20. [PMID: 24371222 DOI: 10.1158/0008-5472.can-13-2444] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The mechanisms by which MUC1 and p120 catenin contribute to progression of cancers from early transformation to metastasis are poorly understood. Here we show that p120 catenin ARM domains 1, 3-5, and 8 mediate interactions between p120 catenin and MUC1, and that these interactions modulate dynamic properties of cell adhesion, motility, and metastasis of pancreatic cancer cells. We also show that different isoforms of p120 catenin, when coexpressed with MUC1, create cells that exhibit distinct patterns of motility in culture (motility independent of cell adhesion, motility within a monolayer while exchanging contacts with other cells, and unified motility while maintaining static epithelial contacts) and patterns of metastasis. The results provide new insight into the dynamic interplay between cell adhesion and motility and the relationship of these to the metastatic process.
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Affiliation(s)
- Xiang Liu
- Authors' Affiliations: Eppley Institute for Research in Cancer and Allied Disease; Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska; Department of Gynecologic Oncology and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California
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32
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Rapidly progressive symptom development of pulmonary arterial hypertension: a case report of Trousseau syndrome. Heart Vessels 2013; 29:873-7. [PMID: 24275907 DOI: 10.1007/s00380-013-0446-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 11/08/2013] [Indexed: 02/03/2023]
Abstract
Trousseau syndrome is most commonly defined as a hypercoagulability syndrome associated with mucin-producing adenocarcinoma. We report here a rare case of Trousseau syndrome presenting as pulmonary arterial hypertension. The patient complained of cough and increasing exertional dyspnea. Rapidly progressive symptom development of pulmonary arterial hypertension accompanied by right heart failure was observed, and the patient died on hospital day 2. An autopsy revealed Krukenberg tumors on both ovaries and a signet-ring cell gastric carcinoma. In the lungs there was tumor embolism with signet-ring cells to some extent, but the peripheral pulmonary arteries were occupied primarily by pulmonary embolism with platelets, fibroblasts, and fibrotic organized thrombi.
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Do SI, Kim K, Kim DH, Chae SW, Park YL, Park CH, Sohn JH. Associations between the Expression of Mucins (MUC1, MUC2, MUC5AC, and MUC6) and Clinicopathologic Parameters of Human Breast Ductal Carcinomas. J Breast Cancer 2013; 16:152-8. [PMID: 23843846 PMCID: PMC3706859 DOI: 10.4048/jbc.2013.16.2.152] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 04/29/2013] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Mucins are members of the glycoprotein family expressed in benign and malignant epithelial cells. The aim of this study is to evaluate the relationships between the expression of mucins in breast ductal carcinoma and clinicopathologic parameters. METHODS We constructed tumor microarrays based on 240 cases of invasive ductal carcinoma and 40 cases of ductal carcinoma in situ (DCIS) using formalin fixed, paraffin embedded tissues. We examined the expressions of MUC1, MUC2, MUC5AC, and MUC6 by immunohistochemistry. RESULTS MUC1 demonstrated cytoplasmic, membranous, apical, and combinative expressions. Other mucins demonstrated cytoplasmic expression. In invasive ductal carcinoma, MUC1, MUC2, MUC5AC, and MUC6 were expressed in 93.6%, 6.2%, 4.8%, and 12.4% of cases, respectively; these rates were slightly, but not significantly, higher than observed in cases of DCIS. MUC1 expression was associated with estrogen receptor (ER) expression and negative MUC1 expression was associated with triple negativity. MUC6 expression was correlated with higher histologic grade, lymphatic invasion, lymph node metastasis, and HER2 positivity. No associations with any other clinicopathologic parameters were observed. CONCLUSION Most invasive ductal carcinomas of the breast express MUC1, and this expression is associated with ER expression. MUC6 expression is correlated with some clinicopathologic parameters that are indicators of poor prognosis. To evaluate the role of MUC6 as a potential biomarker, further studies are warranted.
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Affiliation(s)
- Sung-Im Do
- Department of Pathology, Breast and Thyroid Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Abstract
Mucin-type O-glycosylation is an evolutionarily conserved protein modification present on membrane-bound and secreted proteins. Aberrations in O-glycosylation are responsible for certain human diseases and are associated with disease risk factors. Recent studies have demonstrated essential roles for mucin-type O-glycosylation in protein secretion, stability, processing, and function. Here, we summarize our current understanding of the diverse roles of mucin-type O-glycosylation during eukaryotic development. Appreciating how this conserved modification operates in developmental processes will provide insight into its roles in human disease and disease susceptibilities.
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Affiliation(s)
- Duy T Tran
- Developmental Glycobiology Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4370, USA
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35
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Mucin 6 and Tn Antigen Expression in Canine Mammary Tumours: Correlation with Pathological Features. J Comp Pathol 2012; 147:410-8. [DOI: 10.1016/j.jcpa.2012.03.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 02/10/2012] [Accepted: 03/28/2012] [Indexed: 11/20/2022]
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Evaluation of pancreatic intraepithelial neoplasia and mucin expression in normal pancreata. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2012; 19:242-8. [PMID: 21644061 DOI: 10.1007/s00534-011-0401-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/PURPOSE It has been suggested that pancreatic ductal adenocarcinoma (PDAC) and pancreatic intraepithelial neoplasia (PanIN) are closely related, but several reports indicate PanIN lesions can also be found in normal pancreata (normal PanINs). We examined differences in mucin expression between normal PanIN lesions and PanINs in PDACs (PDAC PanINs). METHODS We examined 54 autopsied normal pancreata and eight autopsied PDACs for PanIN lesions; graded the pancreata specimens as PanIN-1A (non-papillary hyperplasia), PanIN-1B (papillary hyperplasia), PanIN-2 (atypical hyperplasia) or PanIN-3 (carcinoma in situ); and tested the PanIN lesions for expression of MUC1 (pan-epithelial membrane-associated mucin) and MUC5AC (gastric secretory mucin) which were both previously detected in PDACs. RESULTS In normal PanIN-1A, PanIN-1B and PanIN-2 specimens, MUC1 was expressed in 2.8, 10.5 and 9.1%, respectively, compared to 19.1, 27.6 and 13.0% in PDAC PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively. MUC5AC was expressed in 41.0, 65.7 and 36.4% of normal PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively, and in 80.9, 75.8 and 78.3% of PDAC PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively. Differences in the frequency of MUC1 expression were significant between normal and PDAC PanIN-1A (p < 0.0001) and PanIN-1B (p < 0.05); and differences in the frequency of MUC5AC expression were significant between normal and PDAC PanIN-1A (p < 0.0001) and PanIN-2 (p < 0.05). CONCLUSIONS Normal PanIN and PDAC PanIN lesions differed in the rates of MUC1 and MUC5AC expression.
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Kakita K, Tsuda T, Suzuki N, Nakamura S, Nambu H, Hashimoto S. A stereocontrolled construction of 2-azido-2-deoxy-1,2-cis-α-galactosidic linkages utilizing 2-azido-4,6-O-benzylidene-2-deoxygalactopyranosyl diphenyl phosphates: stereoselective synthesis of mucin core 5 and core 7 structures. Tetrahedron 2012. [DOI: 10.1016/j.tet.2012.04.059] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Zhang Y, Muthana SM, Farnsworth D, Ludek O, Adams K, Barchi JJ, Gildersleeve JC. Enhanced epimerization of glycosylated amino acids during solid-phase peptide synthesis. J Am Chem Soc 2012; 134:6316-25. [PMID: 22390544 PMCID: PMC3324660 DOI: 10.1021/ja212188r] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Glycopeptides are extremely useful for basic research and clinical applications, but access to structurally defined glycopeptides is limited by the difficulties in synthesizing this class of compounds. In this study, we demonstrate that many common peptide coupling conditions used to prepare O-linked glycopeptides result in substantial amounts of epimerization at the α position. In fact, epimerization resulted in up to 80% of the non-natural epimer, indicating that it can be the major product in some reactions. Through a series of mechanistic studies, we demonstrate that the enhanced epimerization relative to nonglycosylated amino acids is due to a combination of factors, including a faster rate of epimerization, an energetic preference for the unnatural epimer over the natural epimer, and a slower overall rate of peptide coupling. In addition, we demonstrate that use of 2,4,6-trimethylpyridine (TMP) as the base in peptide couplings produces glycopeptides with high efficiency and low epimerization. The information and improved reaction conditions will facilitate the preparation of glycopeptides as therapeutic compounds and vaccine antigens.
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Affiliation(s)
- Yalong Zhang
- Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland, 21702
| | - Saddam M. Muthana
- Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland, 21702
| | - David Farnsworth
- Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland, 21702
| | - Olaf Ludek
- Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland, 21702
| | - Kristie Adams
- Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland, 21702
| | - Joseph J. Barchi
- Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland, 21702
| | - Jeffrey C. Gildersleeve
- Chemical Biology Laboratory, National Cancer Institute, 376 Boyles Street, Building 376, Frederick, Maryland, 21702
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Recent advances in developing synthetic carbohydrate-based vaccines for cancer immunotherapies. Future Med Chem 2012; 4:545-84. [DOI: 10.4155/fmc.11.193] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Cancer cells can often be distinguished from healthy cells by the expression of unique carbohydrate sequences decorating the cell surface as a result of aberrant glycosyltransferase activity occurring within the cell; these unusual carbohydrates can be used as valuable immunological targets in modern vaccine designs to raise carbohydrate-specific antibodies. Many tumor antigens (e.g., GM2, Ley, globo H, sialyl Tn and TF) have been identified to date in a variety of cancers. Unfortunately, carbohydrates alone evoke poor immunogenicity, owing to their lack of ability in inducing T-cell-dependent immune responses. In order to enhance their immunogenicity and promote long-lasting immune responses, carbohydrates are often chemically modified to link to an immunogenic protein or peptide fragment for eliciting T-cell-dependent responses. This review will present a summary of efforts and advancements made to date on creating carbohydrate-based anticancer vaccines, and will include novel approaches to overcoming the poor immunogenicity of carbohydrate-based vaccines.
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Stübke K, Wicklein D, Herich L, Schumacher U, Nehmann N. Selectin-deficiency reduces the number of spontaneous metastases in a xenograft model of human breast cancer. Cancer Lett 2012; 321:89-99. [PMID: 22366582 DOI: 10.1016/j.canlet.2012.02.019] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 02/16/2012] [Accepted: 02/16/2012] [Indexed: 01/02/2023]
Abstract
Metastasis formation is a complex process still poorly understood. Previous work in a colon cancer xenograft model showed that E(ndothelial) and P(latelet) selectins mediate spontaneous metastasis to the lungs. To investigate the functional role of selectins in breast cancer, human DU4475 breast cancer cells were injected subcutaneously into pfp-/-rag2-/- mice and in all their selectin-deficient variants (EP-/-, E-/- and P-/-). Pfp-/-rag2-/- mice as well as all their selectin-deficient variants developed primary tumours and spontaneous metastases. Compared with the wild-type mice, disseminated tumours cells were significantly lower (74% reduction, P=0.046) in the bone marrow of selectin-deficient mice. Pfp-/-rag2-/- mice developed significantly higher numbers of lung metastases (6644.83±741.77) than the E-/- (4053.33±112.58; P=0.002) and the EP-/- pfp-/-rag2-/- mice (4665.65±754.50; P<0.001). The results indicate that E- and P-selectins play a role in spontaneous metastasis formation both into bone marrow and lungs. However, spontaneous metastasis was not completely abrogated, hence additional cell adhesion molecules must be involved in the metastatic spread.
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Affiliation(s)
- Katrin Stübke
- University Medical Center Hamburg-Eppendorf, Center for Experimental Medicine, Department of Anatomy and Experimental Morphology, Hamburg, Germany.
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Hao E, Jensen TJ, Vicente MGH. Synthesis of porphyrin-carbohydrate conjugates using "click" chemistry and their preliminary evaluation in human HEp2 cells. J PORPHYR PHTHALOCYA 2012. [DOI: 10.1142/s1088424609000085] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Using a Cu ( I )-catalyzed carbohydrate azide-alkynylphenylporphyrin cycloaddition (the so-called "click" chemistry), we have synthesized in high yields, a series of four new porphyrin-carbohydrate conjugates containing either one or four galactose or lactose moieties linked via triazole units to a meso-phenyl group of a TPP or tetrabenzoporphyrin (TBP) macrocycle. The time-dependent uptake and subcellular distribution of this series of porphyrin-carbohydrate conjugates were evaluated in human carcinoma HEp2 cells. While the three TPP conjugates accumulated to a similar extent within cells and localized mainly in the ER and endosomes, the TBP-galactose conju gate was the one most efficiently taken up by the HEp2 cells, accumulating approximately 5 times more than the TPP conjugates, and localized preferentially within the cell lysosomes.
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Affiliation(s)
- Erhong Hao
- Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Timothy J. Jensen
- Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
| | - M. Graça H. Vicente
- Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
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Abstract
The extreme size, extensive glycosylation, and gel-forming nature of mucins make them a challenge to work with, and methodologies for the detection of mucins must take into consideration these features to ensure that one obtains both accurate and meaningful results. In understanding and appreciating the nature of mucins, this affords the researcher a valuable toolkit which can be used to full advantage in detecting, quantifying, and visualising mucins. The employment of a combinatorial approach to mucin detection, using antibody, chemical, and lectin detection methods, allows important information to be gleaned regarding the size, extent of glycosylation, specific mucin species, and distribution of mucins within a given sample. In this chapter, the researcher is guided through considerations into the structure of mucins and how this both affects the detection of mucins and can be used to full advantage. Techniques including ELISA, dot/slot blotting, and Western blotting, use of lectins and antibodies in mucin detection on membranes as well as immunohistochemistry and immunofluorescence on both tissues and cells grown on Transwell™ inserts are described. Notes along with each section advice the researcher on best practice and describe any associated limitations of a particular technique from which the researcher can further develop a particular protocol.
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Affiliation(s)
- Ceri A Harrop
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
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Issa SMA, Schulz BL, Packer NH, Karlsson NG. Analysis of mucosal mucins separated by SDS-urea agarose polyacrylamide composite gel electrophoresis. Electrophoresis 2011; 32:3554-63. [DOI: 10.1002/elps.201100374] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 09/23/2011] [Accepted: 09/23/2011] [Indexed: 11/11/2022]
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Geng Y, Marshall JR, King MR. Glycomechanics of the metastatic cascade: tumor cell-endothelial cell interactions in the circulation. Ann Biomed Eng 2011; 40:790-805. [PMID: 22101756 DOI: 10.1007/s10439-011-0463-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Accepted: 11/02/2011] [Indexed: 02/07/2023]
Abstract
Hydrodynamic shear force plays an important role in the leukocyte adhesion cascade that involves the tethering and rolling of cells along the endothelial layer, their firm adhesion or arrest, and their extravasation or escape from the circulatory system by inducing passive deformation, or cell flattening, and microvilli stretching, as well as regulating the expression, distribution, and conformation of adhesion molecules on leukocytes and the endothelial layer. Similarly, the dissemination of circulating tumor cells (CTCs) from the primary tumor sites is believed to involve tethering, rolling, and firm adhesion steps before their eventual extravasation which leads to secondary tumor sites (metastasis). Of particular importance to both the leukocyte adhesion cascade and the extravasation of CTCs, glycoproteins are involved in all three steps (capture, rolling, and firm adhesion) and consist of a variety of important selectin ligands. This review article provides an overview of glycoprotein glycosylation associated with the abnormal glycan expression on cancer cell surfaces, where well-established and novel selectin ligands that are cancer related are discussed. An overview of computational approaches on the effects of fluid mechanical force on glycoprotein mediated cancer cell rolling and adhesion is presented with a highlight of recent flow-based and selectin-mediated cell capturing/enriching devices. Finally, as an important branch of the glycoprotein family, mucins, specifically MUC1, are discussed in the context of their aberrant expression on cancer cells and their role as cancer cell adhesion molecules. Since metastasis relies heavily on glycoprotein interactions in the bloodstream where the fluid shear stress highly regulates cell adhesion forces, it is important to study and understand the glycomechanics of all relevant glycoproteins (well-established and novel) as they relate to the metastatic cascade.
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Affiliation(s)
- Yue Geng
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
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45
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THERKILDSEN MARIANNEHAMILTON. Epithelial salivary gland tumours. An immunohistological and prognostic investigation. APMIS 2011. [DOI: 10.1111/j.1600-0463.1999.tb05379.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Overexpression of MUC1 enhances proangiogenic activity of non-small-cell lung cancer cells through activation of Akt and extracellular signal-regulated kinase pathways. Lung 2011; 189:453-60. [PMID: 21959954 DOI: 10.1007/s00408-011-9327-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Accepted: 09/14/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Angiogenesis is an important process required for tumor progression. Mucin 1 (MUC1) is a transmembrane glycoprotein that is aberrantly upregulated in many types of cancer, including non-small-cell lung cancer (NSCLC). However, the biological significance of MUC1 overexpression in lung cancer angiogenesis is not completely understood. METHODS We showed that enforced expression of MUC1 in two NSCLC cell lines, A549 and NCI-H460, which have a low level of endogenous MUC1, promoted their ability to induce vascular endothelial growth factor (VEGF)-dependent endothelial cell migration and tube formation. RESULTS There was a significant increase in VEGF expression in MUC1-overexpressing NSCLC cells. Moreover, MUC1 overexpression resulted in a marked elevation in phosphorylated Akt and extracellular signal-regulated kinase (ERK)1/2, indicative of activation of both signaling pathways. Most importantly, inhibition of Akt or ERK signaling using specific chemical inhibitors restrained the proangiogenic activity of MUC1-overexpressing NSCLC cells. CONCLUSIONS Taken together, our present data demonstrate that the aberrant upregulation of MUC1 favors tumor angiogenesis in NSCLC, likely through the activation of both Akt and ERK pathways and elevation of VEGF production. MUC1 may thus be a potential antiangiogenic target in NSCLC.
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Overdevest JB, Thomas S, Kristiansen G, Hansel DE, Smith SC, Theodorescu D. CD24 offers a therapeutic target for control of bladder cancer metastasis based on a requirement for lung colonization. Cancer Res 2011; 71:3802-11. [PMID: 21482678 DOI: 10.1158/0008-5472.can-11-0519] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Metastasis is lethal in most bladder cancer patients. Expression of CD24, a glycosyl phosphatidylinositol (GPI)-linked sialoglycoprotein and cancer stem cell marker, is associated with metastatic progression in multiple cancer types, yet the role of CD24 in this process remains unclear. While developing a murine model of human metastatic bladder cancer, we observed that tumor cell CD24 expression correlated with a propensity to metastasize to the lung. Our immunohistochemical evaluation of 60 paired primary and metastatic human bladder cancer samples revealed increased intensity (P < 0.001) and frequency (P < 0.001) of CD24 expression in metastases. To directly evaluate the role of CD24 in metastatic colonization, we manipulated CD24 expression in human bladder cancer cell lines using short hairpin RNA depletion, cDNA overexpression, and fluorescence-activated cell sorting selection. Although suppression of CD24 reduced acute tumor cell retention in the lungs of mice inoculated intravenously with cancer cells, this differential retention was no longer apparent after 24 hours, prompting us to evaluate the role of CD24 in lung colonization. Here, CD24 was found necessary for subsequent development of lung metastases. We next treated clinically detectable lung metastases in mice with anti-CD24 antibody and observed reduced tumor growth and prolonged survival. These findings suggest that CD24 is a lynchpin of metastatic progression and a promising therapeutic target for antimetastatic therapy.
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Affiliation(s)
- Jonathan B Overdevest
- Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA
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Gill DJ, Clausen H, Bard F. Location, location, location: new insights into O-GalNAc protein glycosylation. Trends Cell Biol 2011; 21:149-58. [PMID: 21145746 DOI: 10.1016/j.tcb.2010.11.004] [Citation(s) in RCA: 179] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 11/10/2010] [Accepted: 11/11/2010] [Indexed: 01/04/2023]
Abstract
O-GalNAc glycosylation of proteins confers essential structural, protective and signaling roles in eumetazoans. Addition of O-glycans onto proteins is an extremely complex process that regulates both sites of attachment and the types of oligosaccharides added. Twenty distinct polypeptide GalNAc-transferases (GalNAc-Ts) initiate O-glycosylation and fine-tuning their expression provides a mechanism for regulating this action. Recently, a new mode of regulation has emerged where activation of Src kinase selectively redistributes Golgi-localized GalNAc-Ts to the ER. This relocalization results in a strong increase in the density of O-glycan decoration. In this review, we discuss how different mechanisms can regulate the number and the types of O-glycans decorating proteins. In addition, we speculate how Src-dependent relocation of GalNAc-Ts could play an important role in cancerous cellular transformation.
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Affiliation(s)
- David J Gill
- Institute of Molecular and Cell Biology (IMCB), Proteos, 61 Biopolis Drive, Singapore, 138673
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Sarkar S, Lombardo SA, Herner DN, Talan RS, Wall KA, Sucheck SJ. Synthesis of a Single-Molecule l-Rhamnose-Containing Three-Component Vaccine and Evaluation of Antigenicity in the Presence of Anti-l-Rhamnose Antibodies. J Am Chem Soc 2010; 132:17236-46. [PMID: 21080675 DOI: 10.1021/ja107029z] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Sourav Sarkar
- Department of Chemistry and Department of Medicinal and Biological Chemistry, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States
| | - Steven A. Lombardo
- Department of Chemistry and Department of Medicinal and Biological Chemistry, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States
| | - Danielle N. Herner
- Department of Chemistry and Department of Medicinal and Biological Chemistry, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States
| | - Rommel S. Talan
- Department of Chemistry and Department of Medicinal and Biological Chemistry, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States
| | - Katherine A. Wall
- Department of Chemistry and Department of Medicinal and Biological Chemistry, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States
| | - Steven J. Sucheck
- Department of Chemistry and Department of Medicinal and Biological Chemistry, The University of Toledo, 2801 West Bancroft Street, Toledo, Ohio 43606, United States
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Ang CS, Phung J, Nice EC. The discovery and validation of colorectal cancer biomarkers. Biomed Chromatogr 2010; 25:82-99. [PMID: 21058408 DOI: 10.1002/bmc.1528] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Accepted: 08/23/2010] [Indexed: 12/27/2022]
Abstract
Colorectal cancer is currently the third most common malignancy in the world. Patients have excellent prognosis following surgical resection if their tumour is still localized at diagnosis. By contrast, once the tumour has started to metastasize, prognosis is much poorer. Accurate early detection can therefore significantly reduce the mortality from this disease. However, current tests either lack the required sensitivity and selectivity or are costly and invasive. Improved biomarkers, or panels of biomarkers, are therefore urgently required. We have addressed current screening strategies and potential protein biomarkers that have been proposed. The role of both discovery and hypothesis-driven proteomics approaches for biomarker discovery and validation is discussed. Using such approaches we show how multiple reaction monitoring (MRM) can be successfully developed and used for quantitative multiplexed analysis of potential faecal biomarkers.
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Affiliation(s)
- Ching-Seng Ang
- Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Melbourne, Australia
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