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Dyachenko EI, Bel’skaya LV. Salivary Transmembrane Mucins of the MUC1 Family (CA 15-3, CA 27.29, MCA) in Breast Cancer: The Effect of Human Epidermal Growth Factor Receptor 2 (HER2). Cancers (Basel) 2024; 16:3461. [PMID: 39456554 PMCID: PMC11506585 DOI: 10.3390/cancers16203461] [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: 08/09/2024] [Revised: 10/01/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
The MUC1 family of transmembrane glycoproteins (CA 15-3, CA 27.29, MCA) is aberrantly expressed among patients with breast cancer. Objectives: to measure the level of degradation products of MUC1, including CA 15-3, CA 27.29, and MCA, in the saliva of breast cancer patients and to describe the biochemical processes that influence their expression and the regulation of their biological functions. Methods: The case-control study included three groups (breast cancer, fibroadenomas, and healthy controls). All study participants provided saliva samples strictly before starting treatment. The levels of MUC1, including CA 15-3, CA 27.29, and MCA, free progesterone and estradiol, cytokines (MCP-1, VEGF, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18), and amino acids (Asp, Gln, Gly, His, Leu + Ile, Orn, Phe, Pro, Tyr) were determined. Results: It was shown that the levels of the MUC1 family in the saliva of patients with HER2-positive breast cancer were significantly lower compared to the control group. The level of pro-inflammatory cytokines and the level of free estradiol affected the expression of MUC1. We obtained a reliable relationship between the aggressive nature of tumor growth, an increased level of pro-inflammatory cytokines, a low level of free estradiol, and the suppressed expression of salivary MUC1. Conclusions: Among patients with aggressive breast cancer, a high level of pro-inflammatory cytokines, and a low level of free estradiol, there was an inhibition of the expression of pathologically unchanged glycoprotein MUC1 in saliva.
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Affiliation(s)
| | - Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
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Verhassel A, Kimani M, Gidwani K, Sandholm J, Gawlitza K, Rurack K, Härkönen P. Detection of Tn-antigen in breast and prostate cancer models by VVL-labeled red dye-doped nanoparticles. Nanomedicine (Lond) 2024; 19:2463-2478. [PMID: 39382009 PMCID: PMC11520574 DOI: 10.1080/17435889.2024.2405454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/13/2024] [Indexed: 10/10/2024] Open
Abstract
Aim: Fluorescence detection of breast and prostate cancer cells expressing Tn-antigen, a tumor marker, with Vicia villosa lectin (VVL)-labeled nanoparticles.Materials & methods: Breast and prostate cancer cells engineered to express high levels of Tn-antigen and non-engineered controls were incubated with VVL-labeled or unlabeled red dye-doped silica-coated polystyrene nanoparticles. The binding to cells was studied with flow cytometry, confocal microscopy, and electron microscopy.Results: Flow cytometry showed that the binding of VVL-labeled nanoparticles was significantly higher to Tn-antigen-expressing cancer cells than controls. Confocal microscopy demonstrated that particles bound to the cell surface. According to the correlative light and electron microscopy the particles bound mostly as aggregates.Conclusion: VVL-labeled nanoparticles could provide a new tool for the detection of Tn-antigen-expressing breast and prostate cancer cells.
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Affiliation(s)
- Alejandra Verhassel
- Institute of Biomedicine, University of Turku, Turku, 20520, Finland
- Western Cancer Centre FICAN West, Turku, 20521, Finland
| | - Martha Kimani
- Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und -prüfung (BAM), Berlin,12489, Germany
| | - Kamlesh Gidwani
- Western Cancer Centre FICAN West, Turku, 20521, Finland
- Department of Biochemistry, University of Turku, Turku, 20520, Finland
| | - Jouko Sandholm
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, 20520, Finland
| | - Kornelia Gawlitza
- Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und -prüfung (BAM), Berlin,12489, Germany
| | - Knut Rurack
- Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und -prüfung (BAM), Berlin,12489, Germany
| | - Pirkko Härkönen
- Institute of Biomedicine, University of Turku, Turku, 20520, Finland
- Western Cancer Centre FICAN West, Turku, 20521, Finland
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3
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Yue S, Wang X, Wang L, Li J, Zhou Y, Chen Y, Zhou Z, Yang X, Shi X, Gao S, Wen Z, Zhu X, Wang Y, Yang S. MOTAI: A Novel Method for the Study of O-GalNAcylation and Complex O-Glycosylation in Cancer. Anal Chem 2024; 96:11137-11145. [PMID: 38953491 PMCID: PMC11257061 DOI: 10.1021/acs.analchem.3c05018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 07/04/2024]
Abstract
The Tn antigen, an immature truncated O-glycosylation, is a promising biomarker for cancer detection and diagnosis. However, reliable methods for analyzing O-GalNAcylation and complex O-glycosylation are lacking. Here, we develop a novel method, MOTAI, for the sequential analysis of O-glycosylation using different O-glycoproteases. MOTAI conjugates glycopeptides on a solid support and releases different types of O-glycosylation through sequential enzymatic digestion by O-glycoproteases, including OpeRATOR and IMPa. Because OpeRATOR has less activity on O-GalNAcylation, MOTAI enriches O-GalNAcylation for subsequent analysis. We demonstrate the effectiveness of MOTAI by analyzing fetuin O-glycosylation and Jurkat cell lines. We then apply MOTAI to analyze colorectal cancer and benign colorectal polyps. We identify 32 Tn/sTn-glycoproteins and 43 T/sT-glycoproteins that are significantly increased in tumor tissues. Gene Ontology analysis reveals that most of these proteins are ECM proteins involved in the adhesion process of the intercellular matrix. Additionally, the protein disulfide isomerase CRELD2 has a significant difference in Tn expression, and the abnormally glycosylated T345 and S349 O-glycosylation sites in cancer group samples may promote the secretion of CRELD2 and ultimately tumorigenesis through ECM reshaping. In summary, MOTAI provides a powerful new tool for the in-depth analysis of O-GalNAcylation and complex O-glycosylation. It also reveals the upregulation of Tn/sTn-glycoproteins in colorectal cancer, which may provide new insights into cancer biology and biomarker discovery.
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Affiliation(s)
- Shuang Yue
- Center
for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Jiangsu, 215123, China
| | - Xiaotong Wang
- Department
of Hepatology and Gastroenterology, The
Affiliated Infectious Hospital of Soochow University, Suzhou 215004, China
| | - Lei Wang
- Protein
Metrics LLC, Room 201-01,
Building A, Novasiot, 58 Xiangke Road, Zhangjiang, Shanghai 201203, China
| | - Jiajia Li
- Center
for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Jiangsu, 215123, China
| | - Yufeng Zhou
- Center
for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Jiangsu, 215123, China
| | - Yan Chen
- Center
for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Jiangsu, 215123, China
| | - Zeyang Zhou
- Department
of General Surgery, The Second Affiliated
Hospital of Soochow University, Suzhou 215004, China
| | - Xiaodong Yang
- Department
of General Surgery, The Second Affiliated
Hospital of Soochow University, Suzhou 215004, China
| | - Xiaofeng Shi
- New
England Biolabs, Inc., 240 County Road, Ipswich, Massachusetts 01938, United States
| | - Song Gao
- Jiangsu Key
Laboratory of Marine Biological Resources and Environment, Jiangsu Ocean University, Lianyungang 222005, China
| | - Zhongmin Wen
- Health
Management Center, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Xiaojun Zhu
- Health
Management Center, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Yan Wang
- Mass
Spectrometry Facility, National Institute of Dental and Craniofacial
Research, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Shuang Yang
- Center
for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Jiangsu, 215123, China
- Health
Management Center, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
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4
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Roy R. Cancer cells and viruses share common glycoepitopes: exciting opportunities toward combined treatments. Front Immunol 2024; 15:1292588. [PMID: 38495885 PMCID: PMC10940920 DOI: 10.3389/fimmu.2024.1292588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 02/06/2024] [Indexed: 03/19/2024] Open
Abstract
Aberrant glycosylation patterns of glycoproteins and glycolipids have long been recognized as one the major hallmarks of cancer cells that has led to numerous glycoconjugate vaccine attempts. These abnormal glycosylation profiles mostly originate from the lack of key glycosyltransferases activities, mutations, over expressions, or modifications of the requisite chaperone for functional folding. Due to their relative structural simplicity, O-linked glycans of the altered mucin family of glycoproteins have been particularly attractive in the design of tumor associated carbohydrate-based vaccines. Several such glycoconjugate vaccine formulations have generated potent monoclonal anti-carbohydrate antibodies useful as diagnostic and immunotherapies in the fight against cancer. Paradoxically, glycoproteins related to enveloped viruses also express analogous N- and O-linked glycosylation patterns. However, due to the fact that viruses are not equipped with the appropriate glycosyl enzyme machinery, they need to hijack that of the infected host cells. Although the resulting N-linked glycans are very similar to those of normal cells, some of their O-linked glycan patterns often share the common structural simplicity to those identified on tumor cells. Consequently, given that both cancer cells and viral glycoproteins share both common N- and O-linked glycoepitopes, glycoconjugate vaccines could be highly attractive to generate potent immune responses to target both conditions.
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Affiliation(s)
- René Roy
- Glycosciences and Nanomaterial Laboratory, Université du Québec à Montréal, Montréal, QC, Canada
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Huang Y, Huang X, Wang Z, He F, Huang Z, Chen C, Tang B, Qin M, Wu Y, Long C, Tang W, Mo X, Liu J. Analysis of differences in intestinal flora associated with different BMI status in colorectal cancer patients. J Transl Med 2024; 22:142. [PMID: 38331839 PMCID: PMC10854193 DOI: 10.1186/s12967-024-04903-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 01/14/2024] [Indexed: 02/10/2024] Open
Abstract
BACKGROUND Overweight is known to be an important risk factor for colorectal cancer (CRC), and the differences in intestinal flora among CRC patients with different BMI status have not been clearly defined. The purpose of this study was to elucidate the differences in the abundance, composition and biological function of intestinal flora in CRC patients with different BMI status. METHOD A total of 170 CRC patients were included and grouped according to the BMI data of CRC patients. BMI ≥ 24 kg/m2 was defined as overweight group, and BMI within the range of 18.5-23.9 kg/m2 was defined as normal weight group. Preoperative stool collection of patients in both groups was used for 16S rRNA sequencing. Total RNA was extracted from 17 CRC tumor tissue samples for transcriptome sequencing, and then CIBERSORT algorithm was used to convert the transcriptome data into the relative content matrix of 22 kinds of immune cells, and the correlation between different intestinal flora and immune cells and immune-related genes under different BMI states was analyzed. Finally, we identified BMI-related differential functional pathways and analyzed the correlation between these pathways and differential intestinal flora. RESULT There was no significant difference in α diversity and β diversity analysis between overweight group and normal weight group. Partial least square discriminant analysis (PLS-DA) could divide the flora into two different clusters according to BMI stratification. A total of 33 BMI-related differential flora were identified by linear discriminant effect size analysis (LEfSe), among which Actinomyces, Desulfovibrio and Bacteroides were significantly enriched in overweight group. ko00514: Other types of O-glycan biosynthesis are significantly enriched in overweight group. There was a significant positive correlation between Clostridium IV and Macrophages M2 and T cells regulatory (Tregs). There was a significant negative correlation with Dendritic cells activated and T cells CD4 memory activated. CONCLUSIONS The richness and diversity of intestinal flora of CRC patients may be related to different BMI status, and the enrichment of Actinomyces, Desulphurvibrio and Bacteroides may be related to overweight status of CRC patients. The tumor microenvironment in which BMI-related differential flora resides has different immune landscapes, suggesting that some intestinal flora may affect the biological process of CRC by regulating immune cell infiltration and immune gene expression, but further experiments are needed to confirm this.
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Affiliation(s)
- Yongqi Huang
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Xiaoliang Huang
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Zhen Wang
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Fuhai He
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Zigui Huang
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Chuanbin Chen
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Binzhe Tang
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Mingjian Qin
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Yongzhi Wu
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Chenyan Long
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Weizhong Tang
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China.
| | - Xianwei Mo
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China.
| | - Jungang Liu
- Division of Colorectal and Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China.
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Sun L, Zhang Y, Li W, Zhang J, Zhang Y. Mucin Glycans: A Target for Cancer Therapy. Molecules 2023; 28:7033. [PMID: 37894512 PMCID: PMC10609567 DOI: 10.3390/molecules28207033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/08/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the human body, which can be classified into secreted mucins and transmembrane mucins according to their distributions. The major difference between them is that secreted mucins do not have transmembrane structural domains, and the expression of each mucin is organ and cell-specific. Under physiological conditions, mucin glycans are involved in the composition of the mucus barrier and thus protect the body from infection and injury. However, abnormal expression of mucin glycans can lead to the occurrence of diseases, especially cancer, through various mechanisms. Therefore, targeting mucin glycans for the diagnosis and treatment of cancer has always been a promising research direction. Here, we first summarize the main types of glycosylation (O-GalNAc glycosylation and N-glycosylation) on mucins and the mechanisms by which abnormal mucin glycans occur. Next, how abnormal mucin glycans contribute to cancer development is described. Finally, we summarize MUC1-based antibodies, vaccines, radio-pharmaceuticals, and CAR-T therapies using the best characterized MUC1 as an example. In this section, we specifically elaborate on the recent new cancer therapy CAR-M, which may bring new hope to cancer patients.
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Affiliation(s)
- Lingbo Sun
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Yuhan Zhang
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Wenyan Li
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Jing Zhang
- Medical College of Yan'an University, Yan'an University, Yan'an 716000, China
| | - Yuecheng Zhang
- Key Laboratory of Analytical Technology and Detection of Yan'an, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an 716000, China
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Asao K, Hashida N, Motooka D, Tsukamoto T, Nakamura S, Maruyama K, Nishida K. Fungal dysbiosis and decreased tear mucin at the conjunctiva in patients with conjunctival mucosa-associated lymphoid tissue lymphoma. BMJ Open Ophthalmol 2023; 8:e001360. [PMID: 37777252 PMCID: PMC10546124 DOI: 10.1136/bmjophth-2023-001360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 09/13/2023] [Indexed: 10/02/2023] Open
Abstract
OBJECTIVE This study aimed to examine the differences in the fungal microbiome between patients with conjunctival mucosa-associated lymphoid tissue (MALT) and healthy controls using metagenomic analysis. METHODS AND ANALYSIS This case-control study was conducted at Osaka University Hospital in Osaka, Japan, from April 2015 to March 2022. Twenty-five consecutive patients with conjunctival MALT lymphoma and 25 healthy volunteers were included. Metagenomic analysis using Internal Transcribed Spacer (ITS)1 deep sequencing and hierarchical clustering was performed to investigate differences in the fungal microbiome. To assess tear environmental change, we measured tear mucin concentrations using ELISA. RESULTS Detailed analyses showed fungal dysbiosis and changes in β-diversity within the conjunctiva of patients with conjunctival MALT lymphoma. Hierarchical clustering revealed that the participants could be divided into three clusters according to the Malassezia abundance: cluster I (Malassezia abundance above 70%), cluster II (Malassezia abundance 25%-70%) and cluster II (Malassezia abundance below 25%). Most patients were included in cluster I, whereas most of healthy controls were included in cluster III. The differences were significant. Tear mucin concentrations were significantly lower in patients with MALT compared with healthy controls. CONCLUSION The metagenomic analysis using ITS1 deep sequencing was useful for identifying the differences in commensal fungi between patients with MALT lymphoma and healthy individuals. The increased prevalence of the Malassezia genus and the decreased levels of tear mucin can lead to an allergic response of the conjunctiva, resulting in the pathogenesis associated with conjunctival MALT lymphoma. Therefore, it may be beneficial to initiate treatment when a high abundance Malassezia is detected.
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Affiliation(s)
- Kazunobu Asao
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Noriyasu Hashida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Daisuke Motooka
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Teruhisa Tsukamoto
- Biology and Translational Research Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical. Co. Ltd, Naruto, Tokushima, Japan
| | - Shota Nakamura
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kazuichi Maruyama
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Vision Informatics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kohji Nishida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Alfaro GF, Palombo V, D’Andrea M, Cao W, Zhang Y, Beever J, Muntifering RB, Pacheco WJ, Rodning SP, Wang X, Moisá SJ. Hepatic transcript profiling in beef cattle: Effects of rumen-protected niacin supplementation. PLoS One 2023; 18:e0289409. [PMID: 37535643 PMCID: PMC10399858 DOI: 10.1371/journal.pone.0289409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 07/18/2023] [Indexed: 08/05/2023] Open
Abstract
The objective of our study was to assess the effect of rumen-protected niacin supplementation on the transcriptome of liver tissue in growing Angus × Simmental steers and heifers through RNA-seq analysis. Consequently, we wanted to assess the known role of niacin in the physiological processes of vasodilation, detoxification, and immune function in beef hepatic tissue. Normal weaned calves (~8 months old) were provided either a control diet or a diet supplemented with rumen-protected niacin (6 g/hd/d) for a 30-day period, followed by a liver biopsy. We observed a significant list of changes at the transcriptome level due to rumen-protected niacin supplementation. Several metabolic pathways revealed potential positive effects to the animal's liver metabolism due to administration of rumen-protected niacin; for example, a decrease in lipolysis, apoptosis, inflammatory responses, atherosclerosis, oxidative stress, fibrosis, and vasodilation-related pathways. Therefore, results from our study showed that the liver transcriptional machinery switched several metabolic pathways to a condition that could potentially benefit the health status of animals supplemented with rumen-protected niacin. In conclusion, based on the results of our study, we can suggest the utilization of rumen-protected niacin supplementation as a nutritional strategy could improve the health status of growing beef cattle in different beef production stages, such as backgrounding operations or new arrivals to a feedlot.
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Affiliation(s)
- Gastón F. Alfaro
- Department of Animal Sciences, Auburn University, Auburn, AL, United States of America
| | - Valentino Palombo
- Department of Agricultural, Environmental and Food Sciences, Università degli Studi del Molise, Campobasso, Italy
| | - Mariasilvia D’Andrea
- Department of Agricultural, Environmental and Food Sciences, Università degli Studi del Molise, Campobasso, Italy
| | - Wenqi Cao
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Yue Zhang
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Jonathan Beever
- Department of Animal Sciences, University of Tennessee, Knoxville, TN, United States of America
| | - Russell B. Muntifering
- Department of Animal Sciences, Auburn University, Auburn, AL, United States of America
- Cooperative Extension Service, University of Kentucky, Kentucky, Lexington, United States of America
| | - Wilmer J. Pacheco
- Department of Poultry Sciences, Auburn University, Auburn, AL, United States of America
| | - Soren P. Rodning
- Department of Animal Sciences, Auburn University, Auburn, AL, United States of America
| | - Xu Wang
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America
| | - Sonia J. Moisá
- Department of Animal Sciences, University of Tennessee, Knoxville, TN, United States of America
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Pinto D, Parameswaran R. Role of Truncated O-GalNAc Glycans in Cancer Progression and Metastasis in Endocrine Cancers. Cancers (Basel) 2023; 15:3266. [PMID: 37444377 DOI: 10.3390/cancers15133266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Glycans are an essential part of cells, playing a fundamental role in many pathophysiological processes such as cell differentiation, adhesion, motility, signal transduction, host-pathogen interactions, tumour cell invasion, and metastasis development. These glycans are also able to exert control over the changes in tumour immunogenicity, interfering with tumour-editing events and leading to immune-resistant cancer cells. The incomplete synthesis of O-glycans or the formation of truncated glycans such as the Tn-antigen (Thomsen nouveau; GalNAcα- Ser/Thr), its sialylated version the STn-antigen (sialyl-Tn; Neu5Acα2-6GalNAcα-Ser/Thr) and the elongated T-antigen (Thomsen-Friedenreich; Galβ1-3GalNAcα-Ser/Thr) has been shown to be associated with tumour progression and metastatic state in many human cancers. Prognosis in various human cancers is significantly poor when they dedifferentiate or metastasise. Recent studies in glycobiology have shown truncated O-glycans to be a hallmark of cancer cells, and when expressed, increase the oncogenicity by promoting dedifferentiation, risk of metastasis by impaired adhesion (mediated by selectins and integrins), and resistance to immunological killing by NK cells. Insight into these truncated glycans provides a complimentary and attractive route for cancer antigen discovery. The recent emergence of immunotherapies against cancers is predicted to harness the potential of using such agents against cancer-associated truncated glycans. In this review, we explore the role of truncated O-glycans in cancer progression and metastasis along with some recent studies on the role of O-glycans in endocrine cancers affecting the thyroid and adrenal gland.
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Affiliation(s)
- Diluka Pinto
- Division of Endocrine Surgery, National University Hospital, Singapore 119074, Singapore
| | - Rajeev Parameswaran
- Division of Endocrine Surgery, National University Hospital, Singapore 119074, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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10
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Liu J, Huang X, Chen C, Wang Z, Huang Z, Qin M, He F, Tang B, Long C, Hu H, Pan S, Wu J, Tang W. Identification of colorectal cancer progression-associated intestinal microbiome and predictive signature construction. J Transl Med 2023; 21:373. [PMID: 37291572 PMCID: PMC10249256 DOI: 10.1186/s12967-023-04119-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/09/2023] [Indexed: 06/10/2023] Open
Abstract
OBJECTIVE The relationship between intestinal microbiome and colorectal cancer (CRC) progression is unclear. This study aims to identify the intestinal microbiome associated with CRC progression and construct predictive labels to support the accurate assessment and treatment of CRC. METHOD The 192 patients included in the study were divided into stage I-II and stage III-IV CRC patients according to the pathological stages, and preoperative stools were collected from both groups for 16S rDNA sequencing of the intestinal microbiota. Pearson correlation and Spearman correlation coefficient analysis were used to analyze the differential intestinal microbiome and the correlation with tumor microenvironment and to predict the functional pathway. XGBoost model (XGB) and Random Forest model (RF) were used to construct the microbiome-based signature. The total RNA extraction from 17 CRC tumor simples was used for transcriptome sequencing. RESULT The Simpson index of intestinal microbiome in stage III-IV CRC were significantly lower than those in stage I-II CRC. Proteus, Parabacteroides, Alistipes and Ruminococcus etc. are significantly enriched genus in feces of CRC patients with stage III-IV. ko00514: Other types of O - glycan biosynthesis pathway is relevant with CRC progression. Alistipes indistinctus was positively correlated with mast cells, immune activators IL-6 and IL6R, and GOBP_PROTEIN_FOLDING_IN_ENDOPLASMIC_RETICULUM dominantly. The Random Forest (RF) model and eXtreme Gradient Boosting (XGBoost) model constructed with 42 CRC progression-associated differential bacteria were effective in distinguishing CRC patients between stage I-II and stage III-IV. CONCLUSIONS The abundance and diversity of intestinal microbiome may increase gradually with the occurrence and progression of CRC. Elevated fetal abundance of Proteus, Parabacteroides, Alistipes and Ruminococcus may contribute to CRC progression. Enhanced synthesis of O - glycans may result in CRC progression. Alistipes indistinctus may play a facilitated role in mast cell maturation by boosting IL-6 production. Alistipes indistinctus may work in the correct folding of endoplasmic reticulum proteins in CRC, reducing ER stress and prompting the survival and deterioration of CRC, which may owe to the enhanced PERK expression and activation of downstream UPR by Alistipes indistinctus. The CRC progression-associated differential intestinal microbiome identified in our study can be served as potential microbial markers for CRC staging prediction.
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Affiliation(s)
- Jungang Liu
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Xiaoliang Huang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Chuanbin Chen
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Zhen Wang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Zigui Huang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Mingjian Qin
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Fuhai He
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Binzhe Tang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Chenyan Long
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China
| | - Hong Hu
- School of Public Health, Guangxi Medical University, Nanning, The People's Republic of China
| | - Shuibo Pan
- School of Public Health, Guangxi Medical University, Nanning, The People's Republic of China
| | - Junduan Wu
- School of Public Health, Guangxi Medical University, Nanning, The People's Republic of China.
| | - Weizhong Tang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, The People's Republic of China.
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11
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Yue S, Wang X, Ge W, Li J, Yang C, Zhou Z, Zhang P, Yang X, Xiao W, Yang S. Deciphering Protein O-GalNAcylation: Method Development and Disease Implication. ACS OMEGA 2023; 8:19223-19236. [PMID: 37305274 PMCID: PMC10249083 DOI: 10.1021/acsomega.3c01653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 04/20/2023] [Indexed: 06/13/2023]
Abstract
Mucin-type O-glycosylation is an important protein post-translational modification that is abundantly expressed on cell surface proteins. Protein O-glycosylation plays a variety of roles in cellular biological functions including protein structure and signal transduction to the immune response. Cell surface mucins are highly O-glycosylated and are the main substance of the mucosal barrier that protects the gastrointestinal or respiratory tract from infection by pathogens or microorganisms. Dysregulation of mucin O-glycosylation may impair mucosal protection against pathogens that can invade cells to trigger infection or immune evasion. Truncated O-glycosylation, also known as Tn antigen or O-GalNAcylation, is highly upregulated in diseases such cancer, autoimmune disorders, neurodegenerative diseases, and IgA nephropathy. Characterization of O-GalNAcylation helps decipher the role of Tn antigen in physiopathology and therapy. However, the analysis of O-glycosylation, specifically the Tn antigen, remains challenging due to the lack of reliable enrichment and identification assays compared to N-glycosylation. Here, we summarize recent advances in analytical methods for O-GalNAcylation enrichment and identification and highlight the biological role of the Tn antigen in various diseases and the clinical implications of identifying aberrant O-GalNAcylation.
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Affiliation(s)
- Shuang Yue
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
- Department
of Endocrinology, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Xiaotong Wang
- Department
of Hepatology and Gastroenterology, The
Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu 215004, China
- Department
of Endocrinology, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Wei Ge
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
| | - Jiajia Li
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
| | - Chuanlai Yang
- Scientific
Research Department, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Zeyang Zhou
- Department
of General Surgery, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Peng Zhang
- Department
of Orthopedics, The Second Affiliated Hospital
of Soochow University, Suzhou, Jiangsu 215004, China
| | - Xiaodong Yang
- Department
of General Surgery, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Wenjin Xiao
- Department
of Endocrinology, The Second Affiliated
Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Shuang Yang
- Center
for Clinical Mass Spectrometry, Department of Pharmaceutical Analysis,
College of Pharmaceutical Sciences, Soochow
University, Suzhou, Jiangsu 215123, China
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12
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Bueno-Sánchez JC, Gómez-Gutiérrez AM, Maldonado-Estrada JG, Quintana-Castillo JC. Expression of placental glycans and its role in regulating peripheral blood NK cells during preeclampsia: a perspective. Front Endocrinol (Lausanne) 2023; 14:1087845. [PMID: 37206444 PMCID: PMC10190602 DOI: 10.3389/fendo.2023.1087845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 03/03/2023] [Indexed: 05/21/2023] Open
Abstract
Preeclampsia is a pregnancy-related multisystem disorder characterized by altered trophoblast invasion, oxidative stress, exacerbation of systemic inflammatory response, and endothelial damage. The pathogenesis includes hypertension and mild-to-severe microangiopathy in the kidney, liver, placenta, and brain. The main mechanisms involved in its pathogenesis have been proposed to limit trophoblast invasion and increase the release of extracellular vesicles from the syncytiotrophoblast into the maternal circulation, exacerbating the systemic inflammatory response. The placenta expresses glycans as part of its development and maternal immune tolerance during gestation. The expression profile of glycans at the maternal-fetal interface may play a fundamental role in physiological pregnancy changes and disorders such as preeclampsia. It is unclear whether glycans and their lectin-like receptors are involved in the mechanisms of maternal-fetal recognition by immune cells during pregnancy homeostasis. The expression profile of glycans appears to be altered in hypertensive disorders of pregnancy, which could lead to alterations in the placental microenvironment and vascular endothelium in pregnancy conditions such as preeclampsia. Glycans with immunomodulatory properties at the maternal-fetal interface are altered in early-onset severe preeclampsia, implying that innate immune system components, such as NK cells, exacerbate the systemic inflammatory response observed in preeclampsia. In this article, we discuss the evidence for the role of glycans in gestational physiology and the perspective of glycobiology on the pathophysiology of hypertensive disorders in gestation.
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Affiliation(s)
- Julio C. Bueno-Sánchez
- Reproduction Group, Department of Physiology and Biochemistry, School of Medicine, Universidad de Antioquia, Medellín, Colombia
- Department of Obstetrics and Gynecology, School of Medicine, Universidad de Antioquia, Medellín, Colombia
- Red Iberoamericana de Alteraciones Vasculares en Trastornos del Embarazo (RIVATREM), Chillan, Chile
| | - Alejandra M. Gómez-Gutiérrez
- Reproduction Group, Department of Physiology and Biochemistry, School of Medicine, Universidad de Antioquia, Medellín, Colombia
| | - Juan G. Maldonado-Estrada
- One Health and Veterinary Innovative Research & Development (OHVRI) Research Group, Escuela de Medicina Veterinaria, Universidad de Antioquia, Medellín, Colombia
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13
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Saeui CT, Shah SR, Fernandez-Gil BI, Zhang C, Agatemor C, Dammen-Brower K, Mathew MP, Buettner M, Gowda P, Khare P, Otamendi-Lopez A, Yang S, Zhang H, Le A, Quinoñes-Hinojosa A, Yarema KJ. Anticancer Properties of Hexosamine Analogs Designed to Attenuate Metabolic Flux through the Hexosamine Biosynthetic Pathway. ACS Chem Biol 2023; 18:151-165. [PMID: 36626752 DOI: 10.1021/acschembio.2c00784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Altered cellular metabolism is a hallmark of cancer pathogenesis and progression; for example, a near-universal feature of cancer is increased metabolic flux through the hexosamine biosynthetic pathway (HBP). This pathway produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a potent oncometabolite that drives multiple facets of cancer progression. In this study, we synthesized and evaluated peracetylated hexosamine analogs designed to reduce flux through the HBP. By screening a panel of analogs in pancreatic cancer and glioblastoma multiform (GBM) cells, we identified Ac4Glc2Bz─a benzyl-modified GlcNAc mimetic─as an antiproliferative cancer drug candidate that down-regulated oncogenic metabolites and reduced GBM cell motility at concentrations non-toxic to non-neoplastic cells. More specifically, the growth inhibitory effects of Ac4Glc2Bz were linked to reduced levels of UDP-GlcNAc and concomitant decreases in protein O-GlcNAc modification in both pancreatic cancer and GBM cells. Targeted metabolomics analysis in GBM cells showed that Ac4Glc2Bz disturbed glucose metabolism, amino acid pools, and nucleotide precursor biosynthesis, consistent with reduced proliferation and other anti-oncogenic properties of this analog. Furthermore, Ac4Glc2Bz reduced the invasion, migration, and stemness of GBM cells. Importantly, normal metabolic functions mediated by UDP-GlcNAc were not disrupted in non-neoplastic cells, including maintenance of endogenous levels of O-GlcNAcylation with no global disruption of N-glycan production. Finally, a pilot in vivo study showed that a potential therapeutic window exists where animals tolerated 5- to 10-fold higher levels of Ac4Glc2Bz than projected for in vivo efficacy. Together, these results establish GlcNAc analogs targeting the HBP through salvage mechanisms as a new therapeutic approach to safely normalize an important facet of aberrant glucose metabolism associated with cancer.
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Affiliation(s)
- Christopher T Saeui
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
| | - Sagar R Shah
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
| | | | - Cissy Zhang
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.,Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21205, United States
| | - Christian Agatemor
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
| | - Kris Dammen-Brower
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
| | - Mohit P Mathew
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
| | - Matthew Buettner
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
| | - Prateek Gowda
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
| | - Pratik Khare
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.,Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21205, United States
| | | | - Shuang Yang
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, United States
| | - Hui Zhang
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, United States
| | - Anne Le
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.,Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21205, United States
| | | | - Kevin J Yarema
- Department of Biomedical Engineering and The Translational Tissue Engineering Center, The Johns Hopkins University and Johns Hopkins School of Medicine, Baltimore, Maryland 21231, United States
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14
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Ramos-Martínez I, Ramos-Martínez E, Cerbón M, Pérez-Torres A, Pérez-Campos Mayoral L, Hernández-Huerta MT, Martínez-Cruz M, Pérez-Santiago AD, Sánchez-Medina MA, García-Montalvo IA, Zenteno E, Matias-Cervantes CA, Ojeda-Meixueiro V, Pérez-Campos E. The Role of B Cell and T Cell Glycosylation in Systemic Lupus Erythematosus. Int J Mol Sci 2023; 24:863. [PMID: 36614306 PMCID: PMC9820943 DOI: 10.3390/ijms24010863] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 01/05/2023] Open
Abstract
Glycosylation is a post-translational modification that affects the stability, structure, antigenicity and charge of proteins. In the immune system, glycosylation is involved in the regulation of ligand-receptor interactions, such as in B-cell and T-cell activating receptors. Alterations in glycosylation have been described in several autoimmune diseases, such as systemic lupus erythematosus (SLE), in which alterations have been found mainly in the glycosylation of B lymphocytes, T lymphocytes and immunoglobulins. In immunoglobulin G of lupus patients, a decrease in galactosylation, sialylation, and nucleotide fucose, as well as an increase in the N-acetylglucosamine bisector, are observed. These changes in glycoisolation affect the interactions of immunoglobulins with Fc receptors and are associated with pericarditis, proteinuria, nephritis, and the presence of antinuclear antibodies. In T cells, alterations have been described in the glycosylation of receptors involved in activation, such as the T cell receptor; these changes affect the affinity with their ligands and modulate the binding to endogenous lectins such as galectins. In T cells from lupus patients, a decrease in galectin 1 binding is observed, which could favor activation and reduce apoptosis. Furthermore, these alterations in glycosylation correlate with disease activity and clinical manifestations, and thus have potential use as biomarkers. In this review, we summarize findings on glycosylation alterations in SLE and how they relate to immune system defects and their clinical manifestations.
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Affiliation(s)
- Ivan Ramos-Martínez
- Departamento de Medicina y Zootecnia de Cerdos, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Edgar Ramos-Martínez
- Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
- Escuela de Ciencias, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68120, Mexico
| | - Marco Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”—Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Armando Pérez-Torres
- Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | | | - María Teresa Hernández-Huerta
- CONACyT, Facultad de Medicina y Cirugía, Universidad Autónoma “Benito Juárez” de Oaxaca (UABJO), Oaxaca 68020, Mexico
| | | | | | | | | | - Edgar Zenteno
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
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15
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Li J, Li X, Guan F. What are the diagnostic capabilities of glycans for breast cancer? Expert Rev Mol Diagn 2023; 23:1-7. [PMID: 36705933 DOI: 10.1080/14737159.2023.2173577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Jing Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Xiang Li
- Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
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16
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Meta-Analysis of RNA-Seq Datasets Identifies Novel Players in Glioblastoma. Cancers (Basel) 2022; 14:cancers14235788. [PMID: 36497269 PMCID: PMC9737249 DOI: 10.3390/cancers14235788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022] Open
Abstract
Glioblastoma is a devastating grade IV glioma with poor prognosis. Identification of predictive molecular biomarkers of disease progression would substantially contribute to better disease management. In the current study, we performed a meta-analysis of different RNA-seq datasets to identify differentially expressed protein-coding genes (PCGs) and long non-coding RNAs (lncRNAs). This meta-analysis aimed to improve power and reproducibility of the individual studies while identifying overlapping disease-relevant pathways. We supplemented the meta-analysis with small RNA-seq on glioblastoma tissue samples to provide an overall transcriptomic view of glioblastoma. Co-expression correlation of filtered differentially expressed PCGs and lncRNAs identified a functionally relevant sub-cluster containing DANCR and SNHG6, with two novel lncRNAs and two novel PCGs. Small RNA-seq of glioblastoma tissues identified five differentially expressed microRNAs of which three interacted with the functionally relevant sub-cluster. Pathway analysis of this sub-cluster identified several glioblastoma-linked pathways, which were also previously associated with the novel cell death pathway, ferroptosis. In conclusion, the current meta-analysis strengthens evidence of an overarching involvement of ferroptosis in glioblastoma pathogenesis and also suggests some candidates for further analyses.
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17
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Morphology of Biomaterials Affect O-Glycosylation of HUVECs. J Funct Biomater 2022; 13:jfb13040235. [PMID: 36412876 PMCID: PMC9680501 DOI: 10.3390/jfb13040235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/06/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Biomaterials have been widely used as substitutes for diseased tissue in surgery and have gained great success and attention. At present, the biocompatibility of biomaterials such as PET woven fabrics is often evaluated both in vitro and in vivo. However, the current experimental methods cannot reveal the relationship between material surfaces and cell adhesion, and few research works have focused on the mechanisms of how the surface morphology of biomaterials affects cell adhesion and proliferation. Thus, it is meaningful to find out how the altered surfaces could affect cell adhesion and growth. In this study, we employed Ar low-temperature plasma treatment technology to create nano-grooves on the warp yarn of PET woven fabrics and seeded human umbellar vein endothelial cells (HUVEC) on these fabrics. We then assessed the O-glycan and N-glycan profiles of the cells grown on different structures of the polyester woven fabrics. The result showed that the surface morphology of polyester woven fabrics could affect the O-glycan profile but not the N-glycan profile of cultured HUVEC. Taken together, the study describes the effects of the surface morphology of biomaterial on the biosynthesis of cellular glycans and may provide new insights into the design and manufacture of biomaterials used as blood vessels based on the expression profiles of O-glycans on cultured cells.
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Bi Y, Jing Y, Guo L. Construction and validation of a prognostic marker and risk model for HCC ultrasound therapy combined with WGCNA identification. Front Genet 2022; 13:1017551. [PMID: 36263426 PMCID: PMC9573990 DOI: 10.3389/fgene.2022.1017551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/12/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a malignant tumor with a highly aggressive and metastatic nature. Ultrasound remains a routine monitoring tool for screening, treatment and post-treatment recheck of HCC. Therefore, it is of great significance to explore the role of ultrasound therapy and related genes in prognosis prediction and clinical diagnosis and treatment of HCC. Methods: Gene co-expression networks were developed utilizing the R package WGCNA as per the expression profiles and clinical features of TCGA HCC samples, key modules were identified by the correlation coefficients between clinical features and modules, and hub genes of modules were determined as per the GS and MM values. Ultrasound treatment differential expression genes were identified using R package limma, and univariate Cox analysis was conducted on the intersection genes of ultrasound differential expression genes and hub genes of key HCC modules to screen the signatures linked with HCC prognosis and construct a risk model. The median risk score was used as the threshold point to classify tumor samples into high- and low-risk groups, and the R package IOBR was used to assess the proportion of immune cells in high- and low-risk groups, R package maftools to assess the genomic mutation differences in high- and low-risk groups, R package GSVA’s ssgsea algorithm to assess the HALLMARK pathway enrichment analysis, and R package pRRophetic to analyze drug sensitivity in patients with HCC. Results: WGCNA analysis based on the expression profiles and clinical data of the TCGA LIHC cohort identified three key modules with two major clinical features associated with HCC. The intersection of ultrasound-related differential genes and module hub genes was selected for univariate Cox analysis to identify prognostic factors significantly associated with HCC, and a risk score model consisting of six signatures was finally developed to analyze the prognosis of individuals with HCC. The risk model showed strength in the training set, overall set, and external validation set. The percentage of immune cell infiltration, genomic mutations, pathway enrichment scores, and chemotherapy drug resistance were significantly different between high- and low-risk groups according to the risk scores. Expression of model genes correlated with tumor immune microenvironment and clinical tumor characteristics while generally differentially expressed in pan-cancer tumor and healthy samples. In the immunotherapy dataset, patients in the high-risk group had a worse prognosis with immunotherapy, indicating that subjects in the low-risk group are more responsive to immunotherapy. Conclusion: The 6-gene signature constructed by ultrasound treatment of HCC combined with WGCNA analysis can be used for prognosis prediction of HCC patients and may become a marker for immune response.
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Affiliation(s)
- Yunlong Bi
- Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Yu Jing
- Department of Oncology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Lingling Guo
- Department of Ultrasound, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
- *Correspondence: Lingling Guo,
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19
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A Complex Connection Between the Diversity of Human Gastric Mucin O-Glycans, Helicobacter pylori Binding, Helicobacter Infection and Fucosylation. Mol Cell Proteomics 2022; 21:100421. [PMID: 36182101 PMCID: PMC9661725 DOI: 10.1016/j.mcpro.2022.100421] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 09/25/2022] [Accepted: 09/26/2022] [Indexed: 01/18/2023] Open
Abstract
Helicobacter pylori colonizes the stomach of half of the human population. Most H. pylori are located in the mucus layer, which is mainly comprised by glycosylated mucins. Using mass spectrometry, we identified 631 glycans (whereof 145 were fully characterized and the remainder assigned as compositions) on mucins isolated from 14 Helicobacter spp.-infected and 14 Helicobacter spp.-noninfected stomachs. Only six identified glycans were common to all individuals, from a total of 60 to 189 glycans in each individual. An increased number of unique glycan structures together with an increased intraindividual diversity and larger interindividual variation were identified among O-glycans from Helicobacter spp.-infected stomachs compared with noninfected stomachs. H. pylori strain J99, which carries the blood group antigen-binding adhesin (BabA), the sialic acid-binding adhesin (SabA), and the LacdiNAc-binding adhesin, bound both to Lewis b (Leb)-positive and Leb-negative mucins. Among Leb-positive mucins, H. pylori J99 binding was higher to mucins from Helicobacter spp.-infected individuals than noninfected individuals. Statistical correlation analysis, binding experiments with J99 wt, and J99ΔbabAΔsabA and inhibition experiments using synthetic glycoconjugates demonstrated that the differences in H. pylori-binding ability among these four groups were governed by BabA-dependent binding to fucosylated structures. LacdiNAc levels were lower in mucins that bound to J99 lacking BabA and SabA than in mucins that did not, suggesting that LacdiNAc did not significantly contribute to the binding. We identified 24 O-glycans from Leb-negative mucins that correlated well with H. pylori binding whereof 23 contained α1,2-linked fucosylation. The large and diverse gastric glycan library identified, including structures that correlated with H. pylori binding, could be used to select glycodeterminants to experimentally investigate further for their importance in host-pathogen interactions and as candidates to develop glycan-based therapies.
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20
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Wang S, Zhang J, Wei F, Li W, Wen L. Facile Synthesis of Sugar Nucleotides from Common Sugars by the Cascade Conversion Strategy. J Am Chem Soc 2022; 144:9980-9989. [PMID: 35583341 DOI: 10.1021/jacs.2c03138] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Sugar nucleotides are essential glycosylation donors in the carbohydrate metabolism. Naturally, most sugar nucleotides are derived from a limited number of common sugar nucleotides by de novo biosynthetic pathways, undergoing single or multiple reactions such as dehydration, epimerization, isomerization, oxidation, reduction, amination, and acetylation reactions. However, it is widely believed that such complex bioconversions are not practical for synthetic use due to the high preparation cost and great difficulties in product isolation. Therefore, most of the discovered sugar nucleotides are not readily available. Here, based on de novo biosynthesis mainly, 13 difficult-to-access sugar nucleotides were successfully prepared from two common sugars D-Man and sucrose in high yields, at a multigram scale, and without the need for tedious purification manipulations. This work demonstrated that de novo biosynthesis, although undergoing complex reactions, is also practical and cost-effective for synthetic use by employing a cascade conversion strategy.
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Affiliation(s)
- Shasha Wang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiang Su 210023, China
| | - Jiabin Zhang
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai 201203, China.,Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Zhongshan, Guangdong 528400, China
| | - Fangyu Wei
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanjin Li
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai 201203, China
| | - Liuqing Wen
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China.,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiang Su 210023, China
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21
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Zheng Y, Zhang J, Meisner J, Li W, Luo Y, Wei F, Wen L. Cofactor-Driven Cascade Reactions Enable the Efficient Preparation of Sugar Nucleotides. Angew Chem Int Ed Engl 2022; 61:e202115696. [PMID: 35212445 DOI: 10.1002/anie.202115696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Indexed: 12/14/2022]
Abstract
Glycosylation is catalyzed by glycosyltransferases using sugar nucleotides or occasionally lipid-linked phosphosugars as donors. However, only very few common sugar nucleotides that occur in humans can be obtained readily, while the majority of sugar nucleotides that exist in bacteria, plants, archaea, or viruses cannot be synthesized in sufficient quantities by either enzymatic or chemical synthesis. The limited availability of such rare sugar nucleotides is one of the major obstacles that has greatly hampered progress in glycoscience. Herein we describe a general cofactor-driven cascade conversion strategy for the efficient synthesis of sugar nucleotides. The described strategy allows the large-scale preparation of rare sugar nucleotides from common sugars in high yields and without the need for tedious purification processes.
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Affiliation(s)
- Yuan Zheng
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jiabin Zhang
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, China.,Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Zhongshan, Guangdong, 528400, China
| | | | - Wanjin Li
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yawen Luo
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fangyu Wei
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Liuqing Wen
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
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22
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Xiao S, Yang C, Zhang Y, Lai C. Downregulation of B3GNT6 is a predictor of poor outcomes in patients with colorectal cancer. World J Surg Oncol 2022; 20:110. [PMID: 35387659 PMCID: PMC8988341 DOI: 10.1186/s12957-022-02561-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/10/2022] [Indexed: 12/03/2022] Open
Abstract
Background The B3GNT6 protein is a member of the O-GlcNAc transferase (OGT) family and is responsible for the production of the core 3 structure of O-glycans. It is generally expressed in the gastrointestinal (GI) tract; however, its clinical significance in colorectal cancer remains largely unexplored. Methods We obtained mRNA transcriptomic sequencing data from 3 gene expression omnibus (GEO) datasets (GSE37182, GSE39582, GSE103512) and The Cancer Genome Atlas (TCGA) to compare the B3GNT6 mRNA levels between colorectal cancer and normal tissues and further evaluate its value as a prognostic marker in colorectal cancer. We further validated this at the protein level in our cohort using immunohistochemical staining of B3GNT6 as well as the Human Protein Atlas online database. Results B3GNT6 expression was downregulated in colorectal cancer tissues as compared to that in the normal tissues at both mRNA and protein levels. Downregulation of B3GNT6 expression was found to be associated with poor overall survival in patients with colorectal cancer as per the data in GSE39582 and TCGA databases. Low B3GNT6 mRNA levels were significantly associated with chromosome instability (CIN) and KRAS mutations in patients with colorectal cancer. Gene set enrichment analysis (GSEA) revealed that low B3GNT6 expression levels in colorectal cancer were associated with increased proteasome activity. Conclusions The results of this study demonstrate that low expression of B3GNT6 is a potential biomarker for poor outcomes in patients with CRC. Moreover, the low expression of B3GNT6 may indicate more frequent activation of the KRAS/ERK signaling pathway, high CIN, and increased proteasomal activity. These novel findings may prove helpful for molecular diagnosis and provide a new therapeutic target for colorectal cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-022-02561-x.
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Affiliation(s)
- Shihan Xiao
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China.,Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China.,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China
| | - Chen Yang
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China.,Department of Colorectal Surgery, 1st Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang Province, China
| | - Yang Zhang
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China.,Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China.,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China
| | - Chen Lai
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China. .,Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China. .,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital of Central South University, Changsha, 410000, Hunan Province, China.
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23
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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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24
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Johnson SE, Galan MC. Synthesis of 2-deoxy mucin-type O-glycan analogues as biological probes. Carbohydr Res 2022; 514:108542. [DOI: 10.1016/j.carres.2022.108542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/07/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
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25
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Wen L, Zheng Y, Zhang J, Meisner J, Li W, Luo Y, Wei F. Cofactor‐Driven Cascade Reactions Enable the Efficient Preparation of Sugar Nucleotides. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202115696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Liuqing Wen
- Shanghai Institute of Materia Medica Chinese Academy of Sciences Chemistry 501 Haike Road 30303 shanghai CHINA
| | - Yuan Zheng
- Shanghai Institute of Materia Medica Chinese Academy of Sciences Carbohydrate-based drug research center CHINA
| | - Jiabinq Zhang
- Shanghai Institute of Materia Medica Chinese Academy of Sciences Carbohydrate-based drug research center CHINA
| | | | - Wanjin Li
- Shanghai Institute of Materia Medica Chinese Academy of Sciences carbohydrate-based drug research center CHINA
| | - Yawen Luo
- Shanghai Institute of Materia Medica Chinese Academy of Sciences cArbohydrate-based drug research center CHINA
| | - Fangyu Wei
- Shanghai Institute of Materia Medica Chinese Academy of Sciences carbohydrate-based drug research center CHINA
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26
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Xia T, Xiang T, Xie H. Update on the role of C1GALT1 in cancer (Review). Oncol Lett 2022; 23:97. [PMID: 35154428 PMCID: PMC8822393 DOI: 10.3892/ol.2022.13217] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/17/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer remains one of the most difficult diseases to treat. In the quest for early diagnoses to improve patient survival and prognosis, targeted therapies have become a hot research topic in recent years. Glycosylation is the most common posttranslational modification in mammalian cells. Core 1β1,3-galactosyltransferase (C1GALT1) is a key glycosyltransferase in the glycosylation process and is the key enzyme in the formation of the core 1 structure on which most complex and branched O-glycans are formed. A recent study reported that C1GALT1 was aberrantly expressed in tumors. In cancer cells, C1GALT1 is regulated by different factors. In the present review, the expression of C1GALT1 in different tumors and its possible molecular mechanisms of action are described and the role of C1GALT1 in cancer development is discussed.
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Affiliation(s)
- Tong Xia
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ting Xiang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hailong Xie
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
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27
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Tvaroška I. Glycosyltransferases as targets for therapeutic intervention in cancer and inflammation: molecular modeling insights. CHEMICAL PAPERS 2022. [DOI: 10.1007/s11696-021-02026-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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28
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Hegde P, B R S, Ballal S, Swamy BM, Inamdar SR. Rhizoctonia bataticola lectin induces apoptosis and inhibits metastasis in ovarian cancer cells by interacting with CA 125 antigen differentially expressed on ovarian cells. Glycoconj J 2021; 38:669-688. [PMID: 34748163 DOI: 10.1007/s10719-021-10027-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/15/2021] [Accepted: 10/14/2021] [Indexed: 10/19/2022]
Abstract
A N-glycan specific lectin from Rhizoctonia bataticola [RBL] was shown to induce growth inhibitory and apoptotic effect in human ovarian, colon and leukemic cells but mitogenic effect on normal PBMCs as reported earlier, revealing its clinical potential. RBL has unique specificity for high mannose tri and tetra antennary N-glycans, expressed in ovarian cancer and also recognizes glycans which are part of CA 125 antigen, a well known ovarian cancer marker. Hence, in the present study diagnostic and therapeutic potential of RBL was investigated using human ovarian epithelial cancer SKOV3 and OVCAR3 cells known for differentially expressing CA 125. RBL binds differentially to human ovarian normal, cyst and cancer tissues. Flow cytometry, western blot analysis of membrane proteins showed the competitive binding of RBL and CA 125 antibody for the same binding sites on SKOV3 and OVCAR3 cells. RBL has strong binding to both SKOV3 and OVCAR3 cells with MFI of 173 and 155 respectively. RBL shows dose and time dependent growth inhibitory effect with IC50 of 2.5 and 8 μg/mL respectively for SKOV3 and OVCAR3 cells. RBL induces reproductive cell death, morphological changes, nuclear degradation and increased release of ROS in SKOV3 and OVCAR3 cells leading to cell death. This is also supported by increase in hypodiploid population, altered MMP leading to apoptosis possibly involving intrinsic pathway. Adhesion, wound healing, invasion and migration assays demonstrated anti-metastasis effect of RBL apart from its growth inhibitory effect. These results show the promising potential of RBL both as a diagnostic and therapeutic agent.
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Affiliation(s)
- Prajna Hegde
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Sindhura B R
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Suhas Ballal
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Bale M Swamy
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India
| | - Shashikala R Inamdar
- Department of Studies in Biochemistry, Karnatak University, Dharwad-580003, Karnatak, India.
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29
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McDermott M, Cerullo AR, Parziale J, Achrak E, Sultana S, Ferd J, Samad S, Deng W, Braunschweig AB, Holford M. Advancing Discovery of Snail Mucins Function and Application. Front Bioeng Biotechnol 2021; 9:734023. [PMID: 34708024 PMCID: PMC8542881 DOI: 10.3389/fbioe.2021.734023] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/06/2021] [Indexed: 01/12/2023] Open
Abstract
Mucins are a highly glycosylated protein family that are secreted by animals for adhesion, hydration, lubrication, and other functions. Despite their ubiquity, animal mucins are largely uncharacterized. Snails produce mucin proteins in their mucous for a wide array of biological functions, including microbial protection, adhesion and lubrication. Recently, snail mucins have also become a lucrative source of innovation with wide ranging applications across chemistry, biology, biotechnology, and biomedicine. Specifically, snail mucuses have been applied as skin care products, wound healing agents, surgical glues, and to combat gastric ulcers. Recent advances in integrated omics (genomic, transcriptomic, proteomic, glycomic) technologies have improved the characterization of gastropod mucins, increasing the generation of novel biomaterials. This perspective describes the current research on secreted snail mucus, highlighting the potential of this biopolymer, and also outlines a research strategy to fulfill the unmet need of examining the hierarchical structures that lead to the enormous biological and chemical diversity of snail mucus genes.
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Affiliation(s)
- Maxwell McDermott
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - Antonio R Cerullo
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - James Parziale
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - Eleonora Achrak
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - Sharmin Sultana
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - Jennifer Ferd
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - Safiyah Samad
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - William Deng
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States
| | - Adam B Braunschweig
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States.,Advanced Science Research Center, Graduate Center of New York, Graduate Department of Biochemistry, New York, NY, United States.,PhD Programs in Biochemistry and Chemistry Graduate Center of the City University of New York, New York, NY, United States
| | - Mandë Holford
- Department of Chemistry and Biochemistry, Hunter College, New York, NY, United States.,PhD Programs in Biochemistry and Chemistry Graduate Center of the City University of New York, New York, NY, United States.,PhD Program in Biology Graduate Center of the City University of New York, New York, NY, United States.,Department of Invertebrate Zoology, The American Museum of Natural History, New York, NY, United States
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30
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Lin YL, Li Y. The Biological Synthesis and the Function of Mucin 2 in Pseudomyxoma Peritonei. Cancer Manag Res 2021; 13:7909-7917. [PMID: 34703312 PMCID: PMC8527350 DOI: 10.2147/cmar.s324982] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/11/2021] [Indexed: 11/25/2022] Open
Abstract
Excessive mucus secretion is the most prominent feature of pseudomyxoma peritonei (PMP), which often leads to significant increase in abdominal circumference, intractable abdominal pain, progressive intestinal obstruction, abdominal organ adhesions, and cachexia. Excessive mucus secretion is also the main cause of death. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the recommended treatment for PMP. However, recurrence is frequently observed even after CRS and HIPEC, presenting similar clinical manifestations. Mucin 2 (MUC2) is the main type of mucin in PMP and plays a key role in the progressive sclerosis of mucus. To comprehensively demonstrate the biosynthetic process and molecular features of MUC2 and to provide new directions for the development of PMP mucolytic strategies, this review systematically summarizes the molecular biology of MUC2, including MUC2 gene structure, transcription, translation, post-translational modification, tertiary structure, and factors regulating mucus viscoelasticity. The results show that MUC2 is a highly glycosylated protein, with glycan accounts for 80% to 90% of the dry weight. The assembly pattern of MUC2 is highly complicated, presenting a bead-like filament. Salt concentration, pH, mucin concentration and trefoil factor family may contribute to the increase in mucus viscoelasticity and sclerosis, which could be used to develop drugs to soften or even dissolve mucus in the future.
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Affiliation(s)
- Yu-Lin Lin
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University (Beijing Technical Training Base of Tumor Deep Hyperthermia and Whole-Body Hyperthermia), Department of Oncology, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University (Beijing Technical Training Base of Tumor Deep Hyperthermia and Whole-Body Hyperthermia), Department of Oncology, Capital Medical University, Beijing, 100038, People's Republic of China
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31
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Wilkinson H, Thomsson KA, Rebelo AL, Hilliard M, Pandit A, Rudd PM, Karlsson NG, Saldova R. The O-Glycome of Human Nigrostriatal Tissue and Its Alteration in Parkinson's Disease. J Proteome Res 2021; 20:3913-3924. [PMID: 34191522 PMCID: PMC8353623 DOI: 10.1021/acs.jproteome.1c00219] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Indexed: 12/31/2022]
Abstract
O-Glycosylation changes in misfolded proteins are of particular interest in understanding neurodegenerative conditions such as Parkinson's disease (PD) and incidental Lewy body disease (ILBD). This work outlines optimizations of a microwave-assisted nonreductive release to limit glycan degradation and employs this methodology to analyze O-glycosylation on the human striatum and substantia nigra tissue in PD, ILBD, and healthy controls, working alongside well-established reductive release approaches. A total of 70 O-glycans were identified, with ILBD presenting significantly decreased levels of mannose-core (p = 0.017) and glucuronylated structures (p = 0.039) in the striatum and PD presenting an increase in sialylation (p < 0.001) and a decrease in sulfation (p = 0.001). Significant increases in sialylation (p = 0.038) in PD were also observed in the substantia nigra. This is the first study to profile the whole nigrostriatal O-glycome in healthy, PD, and ILBD tissues, outlining disease biomarkers alongside benefits of employing orthogonal techniques for O-glycan analysis.
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Affiliation(s)
- Hayden Wilkinson
- NIBRT
GlycoScience Group, National Institute for
Bioprocessing, Research and Training, Blackrock, Dublin A94 X099, Ireland
- CÚRAM,
SFI Research Centre for Medical Devices, National University of Ireland, Galway, Galway H91 W2TY, Ireland
- UCD
School of Medicine, College of Health and Agricultural Science, University College Dublin, Dublin D07 A8NN, Ireland
| | - Kristina A. Thomsson
- Department
of Medical Biochemistry and Cell Biology, Institute of Biomedicine,
Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden
| | - Ana L. Rebelo
- CÚRAM,
SFI Research Centre for Medical Devices, National University of Ireland, Galway, Galway H91 W2TY, Ireland
| | - Mark Hilliard
- NIBRT
GlycoScience Group, National Institute for
Bioprocessing, Research and Training, Blackrock, Dublin A94 X099, Ireland
| | - Abhay Pandit
- CÚRAM,
SFI Research Centre for Medical Devices, National University of Ireland, Galway, Galway H91 W2TY, Ireland
| | - Pauline M. Rudd
- NIBRT
GlycoScience Group, National Institute for
Bioprocessing, Research and Training, Blackrock, Dublin A94 X099, Ireland
| | - Niclas G. Karlsson
- Department
of Medical Biochemistry and Cell Biology, Institute of Biomedicine,
Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden
- Department
of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, Oslo 0167, Norway
| | - Radka Saldova
- NIBRT
GlycoScience Group, National Institute for
Bioprocessing, Research and Training, Blackrock, Dublin A94 X099, Ireland
- CÚRAM,
SFI Research Centre for Medical Devices, National University of Ireland, Galway, Galway H91 W2TY, Ireland
- UCD
School of Medicine, College of Health and Agricultural Science, University College Dublin, Dublin D07 A8NN, Ireland
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32
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A semi-automated, high throughput approach for O-glycosylation profiling of in vitro established cancer cell lines by MALDI-FT-ICR MS. Glycoconj J 2021; 38:747-756. [PMID: 34283362 PMCID: PMC8821499 DOI: 10.1007/s10719-021-10003-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/04/2021] [Accepted: 06/02/2021] [Indexed: 12/30/2022]
Abstract
The study of protein O-glycosylation is important in biological research as O-glycans have been reported to regulate a multitude of molecular and cell biology processes occurring in cancer. It is known that alterations in O-glycosylation are involved in the development and progression of cancer. Their easy accessibility makes in vitro established cell lines suitable and useful models for studying biological mechanisms in disease. However, the O-glycosylation analysis of large numbers of samples, as required in systems biology and biomarker discovery studies, is often challenging. In the present study, O-glycans from three human colorectal cancer cell lines and two human pancreatic cancer cell lines were released by semi-automated, high throughput reductive β-elimination and analysed using ultrahigh resolution MALDI-FT-ICR MS. Automated data integration and processing was performed using MassyTools, where the analyte was automatically included for relative quantitation based on a range of selection criteria including signal-to-noise ratio, mass error and isotopic pattern quality scores. A total of 126 O-glycan compositions, ranging from a single monosaccharide to large oligosaccharides exhibiting complex glycan motifs, were detected. The use of ultrahigh resolution MALDI-FTICR MS enabled glycan identification and quantitation in the matrix region of the spectrum. This approach has the potential to be used for O-glycosylation analysis of large numbers of samples, such as patient sample cohorts.
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33
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The role of O-glycosylation in human disease. Mol Aspects Med 2021; 79:100964. [PMID: 33775405 DOI: 10.1016/j.mam.2021.100964] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
O-glycosylation is a highly frequent post-translation modification of proteins, with important functional implications in both physiological and disease contexts. The biosynthesis of O-glycans depends on several layers of regulation of the cellular glycosylation machinery, being organ-, tissue- and cell-specific. This review provides insights on the molecular mechanism underlying O-glycan biosynthesis and modification, and highlights illustrative examples of diseases that are triggered or modulated by aberrant cellular O-glycosylation. Particular relevance is given to genetic disorders of glycosylation, infectious diseases and cancer. Finally, we address the potential of O-glycans and their biosynthetic pathways as targets for novel therapeutic strategies.
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34
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Rodrigues AFG, Ibelli AMG, Peixoto JDO, Cantão ME, de Oliveira HC, Savoldi IR, Souza MR, Mores MAZ, Carreño LOD, Ledur MC. Genes and SNPs Involved with Scrotal and Umbilical Hernia in Pigs. Genes (Basel) 2021; 12:genes12020166. [PMID: 33513662 PMCID: PMC7912685 DOI: 10.3390/genes12020166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/27/2022] Open
Abstract
Hernia is one of the most common defects in pigs. The most prevalent are the scrotal (SH), inguinal (IH) and umbilical (UH) hernias. We compared the inguinal ring transcriptome of normal and SH-affected pigs with the umbilical ring transcriptome of normal and UH-affected pigs to discover genes and pathways involved with the development of both types of hernia. A total of 13,307 transcripts was expressed in the inguinal and 13,302 in the umbilical ring tissues with 94.91% of them present in both tissues. From those, 35 genes were differentially expressed in both groups, participating in 108 biological processes. A total of 67 polymorphisms was identified in the inguinal ring and 76 in the umbilical ring tissue, of which 11 and 14 were novel, respectively. A single nucleotide polymorphism (SNP) with deleterious function was identified in the integrin α M (ITGAM) gene. The microtubule associated protein 1 light chain 3 γ (MAP1LC3C), vitrin (VIT), aggrecan (ACAN), alkaline ceramidase 2 (ACER2), potassium calcium-activated channel subfamily M α 1 (KCNMA1) and synaptopodin 2 (SYNPO2) genes are highlighted as candidates to trigger both types of hernia. We generated the first comparative study of the pig umbilical and inguinal ring transcriptomes, contributing to the understanding of the genetic mechanism involved with these two types of hernia in pigs and probably in other mammals.
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Affiliation(s)
- Ariene Fernanda Grando Rodrigues
- Programa de Pós-Graduação em Zootecnia, Departamento de Zootecnia, Centro de Educação Superior do Oeste (CEO), Universidade do Estado de Santa Catarina, UDESC, 89815-630 Chapecó, Brazil; (A.F.G.R.); (I.R.S.); (M.R.S.)
| | - Adriana Mércia Guaratini Ibelli
- Embrapa Suínos e Aves, Distrito de Tamanduá, 89715-899 Concórdia, Brazil; (A.M.G.I.); (J.d.O.P.); (M.E.C.); (M.A.Z.M.)
- Programa de Pós-Graduação em Ciências Veterinárias, Departamento de Ciências Veterinárias, Universidade Estadual do Centro-Oeste, 85015-430 Guarapuava, Brazil
| | - Jane de Oliveira Peixoto
- Embrapa Suínos e Aves, Distrito de Tamanduá, 89715-899 Concórdia, Brazil; (A.M.G.I.); (J.d.O.P.); (M.E.C.); (M.A.Z.M.)
- Programa de Pós-Graduação em Ciências Veterinárias, Departamento de Ciências Veterinárias, Universidade Estadual do Centro-Oeste, 85015-430 Guarapuava, Brazil
| | - Maurício Egídio Cantão
- Embrapa Suínos e Aves, Distrito de Tamanduá, 89715-899 Concórdia, Brazil; (A.M.G.I.); (J.d.O.P.); (M.E.C.); (M.A.Z.M.)
| | | | - Igor Ricardo Savoldi
- Programa de Pós-Graduação em Zootecnia, Departamento de Zootecnia, Centro de Educação Superior do Oeste (CEO), Universidade do Estado de Santa Catarina, UDESC, 89815-630 Chapecó, Brazil; (A.F.G.R.); (I.R.S.); (M.R.S.)
| | - Mayla Regina Souza
- Programa de Pós-Graduação em Zootecnia, Departamento de Zootecnia, Centro de Educação Superior do Oeste (CEO), Universidade do Estado de Santa Catarina, UDESC, 89815-630 Chapecó, Brazil; (A.F.G.R.); (I.R.S.); (M.R.S.)
- Programa de Pós-Graduação em Zootecnia, Departamento de Zootecnia, Universidade Federal do Rio Grande do Sul, UFRGS, 91540-000 Porto Alegre, Brazil
| | - Marcos Antônio Zanella Mores
- Embrapa Suínos e Aves, Distrito de Tamanduá, 89715-899 Concórdia, Brazil; (A.M.G.I.); (J.d.O.P.); (M.E.C.); (M.A.Z.M.)
| | | | - Mônica Corrêa Ledur
- Programa de Pós-Graduação em Zootecnia, Departamento de Zootecnia, Centro de Educação Superior do Oeste (CEO), Universidade do Estado de Santa Catarina, UDESC, 89815-630 Chapecó, Brazil; (A.F.G.R.); (I.R.S.); (M.R.S.)
- Embrapa Suínos e Aves, Distrito de Tamanduá, 89715-899 Concórdia, Brazil; (A.M.G.I.); (J.d.O.P.); (M.E.C.); (M.A.Z.M.)
- Correspondence: or ; Tel.: +55-49-3441-0411
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Ratan C, Cicily K D D, Nair B, Nath LR. MUC Glycoproteins: Potential Biomarkers and Molecular Targets for Cancer Therapy. Curr Cancer Drug Targets 2021; 21:132-152. [PMID: 33200711 DOI: 10.2174/1568009620666201116113334] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/02/2020] [Accepted: 10/04/2020] [Indexed: 02/08/2023]
Abstract
MUC proteins have great significance as prognostic and diagnostic markers as well as a potential target for therapeutic interventions in most cancers of glandular epithelial origin. These are high molecular weight glycosylated proteins located in the epithelial lining of several tissues and ducts. Mucins belong to a heterogeneous group of large O-glycoproteins that can be either secreted or membrane-bound. Glycosylation, a post-translational modification affects the biophysical, functional and biochemical properties and provides structural complexity for these proteins. Aberrant expression and glycosylation of mucins contribute to tumour survival and proliferation in many cancers, which in turn activates numerous signalling pathways such as NF-kB, ERα, HIF, MAPK, p53, c-Src, Wnt and JAK-STAT, etc. This subsequently induces cancer cell growth, proliferation and metastasis. The present review mainly demonstrates the functional aspects of MUC glycoproteins along with its unique signalling mechanism and role of aberrant glycosylation in cancer progression and therapeutics. The importance of MUC proteins and its subtypes in a wide spectrum of cancers including but not limited to breast cancer, colorectal cancer, endometrial and cervical cancer, lung cancer, primary liver cancer, pancreatic cancer, prostate cancer and ovarian cancer has been exemplified with significance in targeting the same. Several patents associated with the MUC proteins in the field of cancer therapy are also emphasized in the current review.
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Affiliation(s)
- Chameli Ratan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala 682041, India
| | - Dalia Cicily K D
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala 682041, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala 682041, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P. O., Kochi, Kerala 682041, India
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Madunić K, Zhang T, Mayboroda OA, Holst S, Stavenhagen K, Jin C, Karlsson NG, Lageveen-Kammeijer GSM, Wuhrer M. Colorectal cancer cell lines show striking diversity of their O-glycome reflecting the cellular differentiation phenotype. Cell Mol Life Sci 2021; 78:337-350. [PMID: 32236654 PMCID: PMC7867528 DOI: 10.1007/s00018-020-03504-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 02/07/2023]
Abstract
Alterations in protein glycosylation in colorectal cancer (CRC) have been extensively studied using cell lines as models. However, little is known about their O-glycome and the differences in glycan biosynthesis in different cell types. To provide a better understanding of the variation in O-glycosylation phenotypes and their association with other molecular features, an in-depth O-glycosylation analysis of 26 different CRC cell lines was performed. The released O-glycans were analysed on porous graphitized carbon nano-liquid chromatography system coupled to a mass spectrometer via electrospray ionization (PGC-nano-LC-ESI-MS/MS) allowing isomeric separation as well as in-depth structural characterization. Associations between the observed glycan phenotypes with previously reported cell line transcriptome signatures were examined by canonical correlation analysis. Striking differences are observed between the O-glycomes of 26 CRC cell lines. Unsupervized principal component analysis reveals a separation between well-differentiated colon-like and undifferentiated cell lines. Colon-like cell lines are characterized by a prevalence of I-branched and sialyl Lewis x/a epitope carrying glycans, while most undifferentiated cell lines show absence of Lewis epitope expression resulting in dominance of truncated α2,6-core sialylated glycans. Moreover, the expression of glycan signatures associates with the expression of glycosyltransferases that are involved in their biosynthesis, providing a deeper insight into the regulation of glycan biosynthesis in different cell types. This untargeted in-depth screening of cell line O-glycomes paves the way for future studies exploring the role of glycosylation in CRC development and drug response leading to discovery of novel targets for the development of anti-cancer antibodies.
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Affiliation(s)
- Katarina Madunić
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands
| | - Tao Zhang
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands
| | - Oleg A Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands
| | - Stephanie Holst
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands
| | - Kathrin Stavenhagen
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands
| | - Chunsheng Jin
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Niclas G Karlsson
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands.
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Houvast RD, Vankemmelbeke M, Durrant LG, Wuhrer M, Baart VM, Kuppen PJK, de Geus-Oei LF, Vahrmeijer AL, Sier CFM. Targeting Glycans and Heavily Glycosylated Proteins for Tumor Imaging. Cancers (Basel) 2020; 12:cancers12123870. [PMID: 33371487 PMCID: PMC7767531 DOI: 10.3390/cancers12123870] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Distinguishing malignancy from healthy tissue is essential for oncologic surgery. Targeted imaging during an operation aids the surgeon to operate better. The present tracers for detecting cancer are directed against proteins that are overexpressed on the membrane of tumor cells. This review evaluates the use of tumor-associated sugar molecules as an alternative for proteins to image cancer tissue. These sugar molecules are present as glycans on glycosylated membrane proteins and glycolipids. Due to their location and large numbers per cell, these sugar molecules might be better targets for tumor imaging than proteins. Abstract Real-time tumor imaging techniques are increasingly used in oncological surgery, but still need to be supplemented with novel targeted tracers, providing specific tumor tissue detection based on intra-tumoral processes or protein expression. To maximize tumor/non-tumor contrast, targets should be highly and homogenously expressed on tumor tissue only, preferably from the earliest developmental stage onward. Unfortunately, most evaluated tumor-associated proteins appear not to meet all of these criteria. Thus, the quest for ideal targets continues. Aberrant glycosylation of proteins and lipids is a fundamental hallmark of almost all cancer types and contributes to tumor progression. Additionally, overexpression of glycoproteins that carry aberrant glycans, such as mucins and proteoglycans, is observed. Selected tumor-associated glyco-antigens are abundantly expressed and could, thus, be ideal candidates for targeted tumor imaging. Nevertheless, glycan-based tumor imaging is still in its infancy. In this review, we highlight the potential of glycans, and heavily glycosylated proteoglycans and mucins as targets for multimodal tumor imaging by discussing the preclinical and clinical accomplishments within this field. Additionally, we describe the major advantages and limitations of targeting glycans compared to cancer-associated proteins. Lastly, by providing a brief overview of the most attractive tumor-associated glycans and glycosylated proteins in association with their respective tumor types, we set out the way for implementing glycan-based imaging in a clinical practice.
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Affiliation(s)
- Ruben D. Houvast
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Mireille Vankemmelbeke
- Scancell Limited, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (M.V.); (L.G.D.)
| | - Lindy G. Durrant
- Scancell Limited, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK; (M.V.); (L.G.D.)
- Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Victor M. Baart
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Peter J. K. Kuppen
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Lioe-Fee de Geus-Oei
- Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Biomedical Photonic Imaging Group, University of Twente, 7500 AE Enschede, The Netherlands
| | - Alexander L. Vahrmeijer
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
| | - Cornelis F. M. Sier
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.D.H.); (V.M.B.); (P.J.K.K.); (A.L.V.)
- Percuros BV, 2333 ZA Leiden, The Netherlands
- Correspondence: ; Tel.: +31-752662610
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Mikkola S. Nucleotide Sugars in Chemistry and Biology. Molecules 2020; 25:E5755. [PMID: 33291296 PMCID: PMC7729866 DOI: 10.3390/molecules25235755] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/02/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Abstract
Nucleotide sugars have essential roles in every living creature. They are the building blocks of the biosynthesis of carbohydrates and their conjugates. They are involved in processes that are targets for drug development, and their analogs are potential inhibitors of these processes. Drug development requires efficient methods for the synthesis of oligosaccharides and nucleotide sugar building blocks as well as of modified structures as potential inhibitors. It requires also understanding the details of biological and chemical processes as well as the reactivity and reactions under different conditions. This article addresses all these issues by giving a broad overview on nucleotide sugars in biological and chemical reactions. As the background for the topic, glycosylation reactions in mammalian and bacterial cells are briefly discussed. In the following sections, structures and biosynthetic routes for nucleotide sugars, as well as the mechanisms of action of nucleotide sugar-utilizing enzymes, are discussed. Chemical topics include the reactivity and chemical synthesis methods. Finally, the enzymatic in vitro synthesis of nucleotide sugars and the utilization of enzyme cascades in the synthesis of nucleotide sugars and oligosaccharides are briefly discussed.
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Affiliation(s)
- Satu Mikkola
- Department of Chemistry, University of Turku, 20014 Turku, Finland
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39
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Low Entropy Sub-Networks Prevent the Integration of Metabolomic and Transcriptomic Data. ENTROPY 2020; 22:e22111238. [PMID: 33287006 PMCID: PMC7712986 DOI: 10.3390/e22111238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/23/2020] [Accepted: 10/27/2020] [Indexed: 02/08/2023]
Abstract
The constantly and rapidly increasing amount of the biological data gained from many different high-throughput experiments opens up new possibilities for data- and model-driven inference. Yet, alongside, emerges a problem of risks related to data integration techniques. The latter are not so widely taken account of. Especially, the approaches based on the flux balance analysis (FBA) are sensitive to the structure of a metabolic network for which the low-entropy clusters can prevent the inference from the activity of the metabolic reactions. In the following article, we set forth problems that may arise during the integration of metabolomic data with gene expression datasets. We analyze common pitfalls, provide their possible solutions, and exemplify them by a case study of the renal cell carcinoma (RCC). Using the proposed approach we provide a metabolic description of the known morphological RCC subtypes and suggest a possible existence of the poor-prognosis cluster of patients, which are commonly characterized by the low activity of the drug transporting enzymes crucial in the chemotherapy. This discovery suits and extends the already known poor-prognosis characteristics of RCC. Finally, the goal of this work is also to point out the problem that arises from the integration of high-throughput data with the inherently nonuniform, manually curated low-throughput data. In such cases, the over-represented information may potentially overshadow the non-trivial discoveries.
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40
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Jiang Y, Wen T, Yan R, Kim SR, Stowell SR, Wang W, Wang Y, An G, Cummings RD, Ju T. O-glycans on death receptors in cells modulate their sensitivity to TRAIL-induced apoptosis through affecting on their stability and oligomerization. FASEB J 2020; 34:11786-11801. [PMID: 32692906 DOI: 10.1096/fj.201900053rr] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 01/14/2020] [Accepted: 06/19/2020] [Indexed: 11/11/2022]
Abstract
The TNF-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in cells by signaling through the O-glycosylated death receptors (DR4 and DR5), but the sensitivity to TRAIL-induced apoptosis of cells varies, and the attributes of this phenomenon are complex. Human carcinoma cells often express truncated O-glycans, Tn (GalNAcα1-Ser/Thr), and Sialyl-Tn (Siaα2-6GalNAcα1-Ser/Thr, STn) on their surface glycoproteins, yet molecular mechanisms in terms of advantages for tumor cells to have these truncated O-glycans remain elusive. Normal extended O-glycan biosynthesis is regulated by a specific molecular chaperone Cosmc through assisting of the correct folding of Core 1 β3 Galactosyltransferase (T-synthase). Here, we use tumor cell lines harboring mutations in Cosmc, and therefore expressing Tn and STn antigens to study the role of O-glycans in TRAIL-induced apoptosis. Expression of Tn and STn in tumor cells attenuates their sensitivity to TRAIL treatment; when transfected with wild-type Cosmc, these tumor cells thus express normal extended O-glycans and become more sensitive to TRAIL treatment. Mechanistically, Tn/STn antigens impair homo-oligomerization and stability of DR4 and DR5. These results represent the first mechanistic insight into how O-glycan structures on cell surface modulate their sensitivity to apoptotic stimuli, suggesting expression of Tn/STn may offer tumor cell survival advantages through altering DR4 and/or DR5 activity.
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Affiliation(s)
- Yuliang Jiang
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.,Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Tao Wen
- Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Rui Yan
- Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Su-Ryun Kim
- Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | - Sean R Stowell
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - Wenyi Wang
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Yingchun Wang
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Guangyu An
- Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Richard D Cummings
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.,Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Tongzhong Ju
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.,Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
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Cipollo JF, Parsons LM. Glycomics and glycoproteomics of viruses: Mass spectrometry applications and insights toward structure-function relationships. MASS SPECTROMETRY REVIEWS 2020; 39:371-409. [PMID: 32350911 PMCID: PMC7318305 DOI: 10.1002/mas.21629] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 04/01/2020] [Accepted: 04/05/2020] [Indexed: 05/21/2023]
Abstract
The advancement of viral glycomics has paralleled that of the mass spectrometry glycomics toolbox. In some regard the glycoproteins studied have provided the impetus for this advancement. Viral proteins are often highly glycosylated, especially those targeted by the host immune system. Glycosylation tends to be dynamic over time as viruses propagate in host populations leading to increased number of and/or "movement" of glycosylation sites in response to the immune system and other pressures. This relationship can lead to highly glycosylated, difficult to analyze glycoproteins that challenge the capabilities of modern mass spectrometry. In this review, we briefly discuss five general areas where glycosylation is important in the viral niche and how mass spectrometry has been used to reveal key information regarding structure-function relationships between viral glycoproteins and host cells. We describe the recent past and current glycomics toolbox used in these analyses and give examples of how the requirement to analyze these complex glycoproteins has provided the incentive for some advances seen in glycomics mass spectrometry. A general overview of viral glycomics, special cases, mass spectrometry methods and work-flows, informatics and complementary chemical techniques currently used are discussed. © 2020 The Authors. Mass Spectrometry Reviews published by John Wiley & Sons Ltd. Mass Spec Rev.
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Affiliation(s)
- John F. Cipollo
- Center for Biologics Evaluation and Research, Food and Drug AdministrationSilver SpringMaryland
| | - Lisa M. Parsons
- Center for Biologics Evaluation and Research, Food and Drug AdministrationSilver SpringMaryland
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Liu C, Li Z, Xu L, Shi Y, Zhang X, Shi S, Hou K, Fan Y, Li C, Wang X, Zhou L, Liu Y, Qu X, Che X. GALNT6 promotes breast cancer metastasis by increasing mucin-type O-glycosylation of α2M. Aging (Albany NY) 2020; 12:11794-11811. [PMID: 32559179 PMCID: PMC7343513 DOI: 10.18632/aging.103349] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 05/14/2020] [Indexed: 01/22/2023]
Abstract
Breast cancer is the most lethal malignancy in women. N-acetylgalactosaminyltransferase 6 (GALNT6) is an enzyme which mediates the initial step of mucin-type O-glycosylation, and has been reported to be involved in mammary carcinogenesis. However, the molecular mechanism of GALNT6 in breast cancer metastasis has not been fully explored. In this study, based on online database analyses and tissue microarrays, the overall survival (OS) of breast cancer patients with high expression of GALNT6 was found to be shorter than those with low expression of GALNT6. Also, high GALNT6 expression was positively correlated with advanced pN stage and pTNM stage. GALNT6 was shown to be able to promote the migration and invasion of breast cancer cells, and enhance the level of mucin-type O-glycosylation of substrates in the supernatants of breast cancer cells. Qualitative mucin-type glycosylomics analysis identified α2M as a novel substrate of GALNT6. Further investigation showed that GALNT6 increased O-glycosylation of α2M, and the following activation of the downstream PI3K/Akt signaling pathway was involved in the promotion of migration and invasion of breast cancer cells. This study identified a new substrate of GALNT6 and provides novel understanding of the role of GALNT6 in promoting metastasis and poor prognosis in breast cancer.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Breast/pathology
- Breast/surgery
- Breast Neoplasms/diagnosis
- Breast Neoplasms/mortality
- Breast Neoplasms/pathology
- Breast Neoplasms/surgery
- Breast Neoplasms, Male/diagnosis
- Breast Neoplasms, Male/mortality
- Breast Neoplasms, Male/pathology
- Breast Neoplasms, Male/surgery
- Carcinoma, Ductal, Breast/diagnosis
- Carcinoma, Ductal, Breast/mortality
- Carcinoma, Ductal, Breast/secondary
- Carcinoma, Ductal, Breast/surgery
- Cell Line, Tumor
- Datasets as Topic
- Female
- Follow-Up Studies
- Glycosylation
- Humans
- Kaplan-Meier Estimate
- Male
- Mastectomy
- Middle Aged
- N-Acetylgalactosaminyltransferases/metabolism
- Neoplasm Metastasis/pathology
- Neoplasm Staging
- Phosphatidylinositol 3-Kinases/metabolism
- Prognosis
- Proto-Oncogene Proteins c-akt/metabolism
- Signal Transduction
- Tissue Array Analysis
- alpha-Macroglobulins/metabolism
- Polypeptide N-acetylgalactosaminyltransferase
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Affiliation(s)
- Chang Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
- Department of Internal Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Lu Xu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yu Shi
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiaojie Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Sha Shi
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yibo Fan
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Ce Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiaoxun Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Lu Zhou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China
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Cao Q, Wang N, Ren L, Tian J, Yang S, Cheng H. miR-125a-5p post-transcriptionally suppresses GALNT7 to inhibit proliferation and invasion in cervical cancer cells via the EGFR/PI3K/AKT pathway. Cancer Cell Int 2020; 20:117. [PMID: 32308562 PMCID: PMC7147043 DOI: 10.1186/s12935-020-01209-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/06/2020] [Indexed: 02/08/2023] Open
Abstract
Background The carcinogenesis and progression of cervical cancer is a complex process in which numerous microRNAs are involved. The purpose of this study is to investigate the role of miR-125a-5p in progression of cervical cancer. Methods RT-qPCR was used to detect the expression of miR-125a-5p and GALNT7 in cervical cancer tissues and cell lines. Then, the miR-125a-5p mimic, miR-125a-5p inhibitor, GALNT7 siRNA, or/and pcDNA-GALNT7 were respectively transfected into HeLa and Caski cervical cancer cells, and Cell Counting kit-8 assay, Transwell assay and flow cytometry analysis were respectively used to observe cell proliferation, invasion and apoptosis. Subsequently, luciferase reporter gene assay was employed in confirming the target relationship between miR-125a-5p and GALNT7. MiR-125a-5p mimic or/and pcDNA-GALNT7 were transfected into the cervical cancer cells at the absence of epidermal growth factor (EGF) or not, and the pcDNA-GALNT7 was transfected into the cervical cancer cells at the absence of inhibitors of multiple kinases or not. Furthermore, the effect of miR-125a-5p on tumor growth was also studied using a xenograft model of nude mice. Results MiR-125a-5p was down-regulated in both cervical cancer tissues and cell lines and it inhibited cell proliferation and invasion of cervical cancer cells. MiR-125a-5p directly targeted and post-transcriptionally downregulated GALNT7 that was strongly upregulated in cervical cancer tissues and cell lines. Similar to the effect of miR-125a-5p mimic, silencing GALNT7 inhibited proliferation and invasion of cervical cancer cells. In addition, miR-125a-5p overexpression could counteract both GALNT7- and EGF-induced cell proliferation and invasion. GALNT7 promoted cell proliferation and invasion by activating the EGFR/PI3K/AKT kinase pathway, which could be abated by the inhibitors of the kinases. Moreover, the role of miR-125a-5p inhibited tumor formation in cervical cancer by suppressing the expression of GALNT7 in vivo. Conclusion In conclusion, miR-125a-5p suppressed cervical cancer progression by post-transcriptionally downregulating GALNT7 and inactivating the EGFR/PI3K/AKT pathway.
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Affiliation(s)
- Qinxue Cao
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Ning Wang
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Lu Ren
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Jun Tian
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Shaoqin Yang
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Hailing Cheng
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
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Katoh T, Ojima MN, Sakanaka M, Ashida H, Gotoh A, Katayama T. Enzymatic Adaptation of Bifidobacterium bifidum to Host Glycans, Viewed from Glycoside Hydrolyases and Carbohydrate-Binding Modules. Microorganisms 2020; 8:microorganisms8040481. [PMID: 32231096 PMCID: PMC7232152 DOI: 10.3390/microorganisms8040481] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/16/2020] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
Certain species of the genus Bifidobacterium represent human symbionts. Many studies have shown that the establishment of symbiosis with such bifidobacterial species confers various beneficial effects on human health. Among the more than ten (sub)species of human gut-associated Bifidobacterium that have significantly varied genetic characteristics at the species level, Bifidobacterium bifidum is unique in that it is found in the intestines of a wide age group, ranging from infants to adults. This species is likely to have adapted to efficiently degrade host-derived carbohydrate chains, such as human milk oligosaccharides (HMOs) and mucin O-glycans, which enabled the longitudinal colonization of intestines. The ability of this species to assimilate various host glycans can be attributed to the possession of an adequate set of extracellular glycoside hydrolases (GHs). Importantly, the polypeptides of those glycosidases frequently contain carbohydrate-binding modules (CBMs) with deduced affinities to the target glycans, which is also a distinct characteristic of this species among members of human gut-associated bifidobacteria. This review firstly describes the prevalence and distribution of B. bifidum in the human gut and then explains the enzymatic machinery that B. bifidum has developed for host glycan degradation by referring to the functions of GHs and CBMs. Finally, we show the data of co-culture experiments using host-derived glycans as carbon sources, which underpin the interesting altruistic behavior of this species as a cross-feeder.
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Affiliation(s)
- Toshihiko Katoh
- Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; (T.K.); (M.N.O.); (A.G.)
| | - Miriam N. Ojima
- Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; (T.K.); (M.N.O.); (A.G.)
| | - Mikiyasu Sakanaka
- National Food Institute, Technical University of Denmark, Kemitorvet, DK-2800 Kgs. Lyngby, Denmark;
- Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Nonoichi, Ishikawa 921-8836, Japan
| | - Hisashi Ashida
- Faculty of Biology-Oriented Science and Technology, Kindai University, Kinokawa, Wakayama 649-6493, Japan;
| | - Aina Gotoh
- Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; (T.K.); (M.N.O.); (A.G.)
| | - Takane Katayama
- Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; (T.K.); (M.N.O.); (A.G.)
- Correspondence: ; Tel.: +81-75-753-9233
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Cheng L, Kong C, Walvoort MTC, Faas MM, de Vos P. Human Milk Oligosaccharides Differently Modulate Goblet Cells Under Homeostatic, Proinflammatory Conditions and ER Stress. Mol Nutr Food Res 2020; 64:e1900976. [PMID: 31800974 PMCID: PMC7079026 DOI: 10.1002/mnfr.201900976] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 11/21/2019] [Indexed: 12/14/2022]
Abstract
SCOPE Human milk oligosaccharides (hMOs) have beneficial effects on intestinal barrier function, but the mechanisms of action are not well understood. Here, the effects of hMOs on goblet cells, which indicate that some hMOs may enhance mucus barrier function through direct modulation of goblet cell function, are studied. METHODS AND RESULTS The modulatory effects of 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3-FL), lacto-N-triaose II (LNT2), and galacto-oligosaccharides (GOS) on the expression of goblet cell secretory related genes MUC2, TFF3, and RETNLB, and the Golgi-sulfotransferase genes CHST5 and GAL3ST2 of LS174T are determined by real-time quantitative RT-PCR. 3-FL, LNT2, and GOS-modulated LS174T gene expression profiles in a dose- and time-dependent manner. In addition, the upregulation of MUC2 is confirmed by immunofluorescence staining. Effects of 2'-FL, 3-FL, LNT2, and GOS on gene transcription of LS174T are also assessed during exposure to TNF-α, IL-13, or tunicamycin. During TNF-α challenge, 3-FL and LNT2 enhance MUC2 and TFF3 gene expression. After IL-13 exposure, 2'-FL, 3-FL, and LNT2 all show upregulating effects on MUC2; 3-FL and LNT2 also enhance TFF3 expression. LNT2 significantly reverses Tm-induced downregulation of TFF3, RETNLB, and CHST5. CONCLUSION The findings indicate that hMOs may enhance mucus barrier function through direct modulation of intestinal goblet cells. Effects are structure- and stressor-dependent.
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Affiliation(s)
- Lianghui Cheng
- Immunoendocrinology, Division of Medical BiologyDepartment of Pathology and Medical BiologyUniversity Medical Center GroningenUniversity of GroningenHanzeplein 19700 RBGroningenThe Netherlands
| | - Chunli Kong
- Immunoendocrinology, Division of Medical BiologyDepartment of Pathology and Medical BiologyUniversity Medical Center GroningenUniversity of GroningenHanzeplein 19700 RBGroningenThe Netherlands
| | - Marthe T. C. Walvoort
- Stratingh Institute for Chemistry, Faculty of Science and EngineeringUniversity of Groningen9700 RBGroningenThe Netherlands
| | - Marijke M. Faas
- Immunoendocrinology, Division of Medical BiologyDepartment of Pathology and Medical BiologyUniversity Medical Center GroningenUniversity of GroningenHanzeplein 19700 RBGroningenThe Netherlands
| | - Paul de Vos
- Immunoendocrinology, Division of Medical BiologyDepartment of Pathology and Medical BiologyUniversity Medical Center GroningenUniversity of GroningenHanzeplein 19700 RBGroningenThe Netherlands
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Hou C, Guo D, Yu X, Wang S, Liu T. TMT-based proteomics analysis of the anti-hepatocellular carcinoma effect of combined dihydroartemisinin and sorafenib. Biomed Pharmacother 2020; 126:109862. [PMID: 32120157 DOI: 10.1016/j.biopha.2020.109862] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/18/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC), as the major primary liver cancer, is one of the most prevalent malignant diseases with a high mortality rate worldwide. Prior studies have demonstrated that dihydroartemisinin (DHA), the semisynthetic derivative of artemisinin, possesses anti-HCC activity. The multikinase inhibitor sorafenib has been approved for the treatment of HCC. However, the anti-HCC efficacy of DHA combined with sorafenib has not been reported. In this study, we confirmed the significantly enhanced anti-HCC efficacy of DHA in combination with sorafenib compared with that of each agent alone. Tandem Mass Tag (TMT) peptide labeling coupled with LC-MS/MS was used to quantify the proteins from the control, DHA, sorafenib, and DHA + sorafenib groups. In total, 532, 426, 628 differentially expressed proteins (fold change >1.20 or <0.83 and P-value <0.05) were determined by comparing DHA versus control, sorafenib versus control and DHA + sorafenib versus control groups, respectively. Moreover, optimized screening was performed, and 101 optimized differentially expressed proteins were identified. The results of functional analysis of the optimized differentially expressed proteins suggested that they were enriched in cell components such as membrane-bound vesicles, extracellular vesicles, and organelle lumens, and they were mainly involved in biological processes such as cellular component organization, response to stress, and response to chemicals; in addition, they were related to various molecular functions such as protein binding, chromatin binding and enzyme binding. KEGG pathway analysis showed that the optimized differentially expressed proteins were enriched in pyrimidine metabolism, RNA polymerase, base excision repair, and osteoclast differentiation. Protein-protein interaction (PPI) networks of some of the optimized upregulated proteins suggested that they might not only affect vitamin and fat digestion and absorption but may also be involved in tight junctions. In the PPI network, some of the optimized downregulated proteins were enriched in base excision repair, RNA polymerase, purine metabolism, pyrimidine metabolism and mucin type O-glycan biosynthesis. Overall, this research explored the anti-HCC efficacy of DHA combined with sorafenib by using the TMT-based quantitative proteomics technique and might facilitate the understanding of the related anti-HCC molecular mechanism.
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Affiliation(s)
- Chunying Hou
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Dongqing Guo
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xue Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Shuyan Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Tianhua Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Bhatia R, Gautam SK, Cannon A, Thompson C, Hall BR, Aithal A, Banerjee K, Jain M, Solheim JC, Kumar S, Batra SK. Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Rev 2020; 38:223-236. [PMID: 30618016 DOI: 10.1007/s10555-018-09775-0] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mucins (MUC) protect epithelial barriers from environmental insult to maintain homeostasis. However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis. Mucin-associated sialyl-Tn (sTn) antigens bind to various receptors present on the dendritic cells (DCs), macrophages, and natural killer (NK) cells, resulting in overall immunosuppression by either receptor masking or inhibition of cytolytic activity. MUC1-mediated interaction of tumor cells with innate immune cells hampers cross-presentation of processed antigens on MHC class I molecules. MUC1 and MUC16 bind siglecs and mask Toll-like receptors (TLRs), respectively, on DCs promoting an immature DC phenotype that in turn reduces T cell effector functions. Mucins, such as MUC1, MUC2, MUC4, and MUC16, interact with or form aggregates with neutrophils, macrophages, and platelets, conferring protection to cancer cells during hematological dissemination and facilitate their spread and colonization to the metastatic sites. On the contrary, poor glycosylation of MUC1 and MUC4 at the tandem repeat region (TR) generates cancer-specific immunodominant epitopes. The presence of MUC16 neo-antigen-specific T cell clones and anti-MUC1 antibodies in cancer patients suggests that mucins can serve as potential targets for developing cancer therapeutics. The present review summarizes the molecular events involved in mucin-mediated immunomodulation, and metastasis, as well as the utility of mucins as targets for cancer immunotherapy and radioimmunotherapy.
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Affiliation(s)
- Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Andrew Cannon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Christopher Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Bradley R Hall
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Kasturi Banerjee
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Joyce C Solheim
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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Josenhans C, Müthing J, Elling L, Bartfeld S, Schmidt H. How bacterial pathogens of the gastrointestinal tract use the mucosal glyco-code to harness mucus and microbiota: New ways to study an ancient bag of tricks. Int J Med Microbiol 2020; 310:151392. [DOI: 10.1016/j.ijmm.2020.151392] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/28/2019] [Accepted: 12/06/2019] [Indexed: 12/13/2022] Open
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Du T, Jia X, Dong X, Ru X, Li L, Wang Y, Liu J, Feng G, Wen T. Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44. Cancer Manag Res 2020; 12:511-522. [PMID: 32158257 PMCID: PMC6986418 DOI: 10.2147/cmar.s234735] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/03/2020] [Indexed: 12/24/2022] Open
Abstract
Background Breast cancer remains the most lethal malignancy in women worldwide. Aberrant O-glycosylation is closely related to many human diseases, including breast carcinoma; however, its precise role in cancer development is insufficiently understood. Cosmc is an endoplasmic reticulum-localized chaperone that regulates the O-glycosylation of proteins. Cosmc dysfunction results in inactive T-synthase and expression of truncated O-glycans such as Tn antigen. Here we investigated the impact of Cosmc disruption-mediated aberrant O-glycosylation on breast cancer cell development through in vitro and in vivo experiments. Materials and Methods We deleted the Cosmc gene in two breast cancer cell lines (MCF7, T47D) using the CRISPR/Cas-9 system and then measured the expression levels of Tn antigen. The proliferation of Tn-positive cells was examined by RTCA, colony formation and in vivo experiments. The effects of Cosmc deficiency on glycoprotein CD44 and MAPK pathway were also determined. Results Both in vitro and in vivo studies showed that Cosmc deficiency markedly suppressed breast cancer cell growth compared with the corresponding controls. Mechanistically, Cosmc disruption impaired the protein expression of CD44 and the associated MAPK signaling pathway; the latter plays a crucial role in cell proliferation. Reconstitution of CD44 substantially reversed the observed alterations, confirming that CD44 requires normal O-glycosylation for its proper expression and activation of the related signaling pathway. Conclusion This study showed that Cosmc deficiency-mediated aberrant O-glycosylation suppressed breast cancer cell growth, which was likely mediated by the impairment of CD44 expression.
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Affiliation(s)
- Tan Du
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Xingyuan Jia
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Xichen Dong
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Xiaoli Ru
- Department of Gynecology and Obstetrics Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Lina Li
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Yakun Wang
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Jian Liu
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Guosheng Feng
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Tao Wen
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
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