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1
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Bertok T, Pinkeova A, Lorencova L, Datkova A, Hires M, Jane E, Tkac J. Glycoproteomics of Gastrointestinal Cancers and Its Use in Clinical Diagnostics. J Proteome Res 2025. [PMID: 40368336 DOI: 10.1021/acs.jproteome.5c00095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
Cancer is a leading cause of death worldwide, resulting in substantial economic costs. Because cancer is a complex, heterogeneous group of diseases affecting a variety of cells, its detection may sometimes be difficult. Herein we review a large group of the gastrointestinal cancers (oral, esophageal, stomach, pancreatic, liver, and bowel cancers) and the possibility of using glycans conjugated to protein backbones for less-invasive diagnoses than the commonly used endoscopic approaches. The reality of bacterial N-glycosylation and the effect of epithelial mucosa on gut microbiota are discussed. Current advantages, barriers, and advantages in the prospective use of selected glycomic approaches in clinical practice are also detailed.
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Affiliation(s)
- Tomas Bertok
- Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovak Republic
| | - Andrea Pinkeova
- Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovak Republic
- Glycanostics, Kudlakova 7, 841 01 Bratislava, Slovak Republic
| | - Lenka Lorencova
- Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovak Republic
| | - Anna Datkova
- Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovak Republic
| | - Michal Hires
- Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovak Republic
| | - Eduard Jane
- Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovak Republic
- Glycanostics, Kudlakova 7, 841 01 Bratislava, Slovak Republic
| | - Jan Tkac
- Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovak Republic
- Glycanostics, Kudlakova 7, 841 01 Bratislava, Slovak Republic
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2
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Xiubing C, Huazhen L, Xueyan W, Jing N, Qing L, Haixing J, Shanyu Q, Jiefu L. SERPINA1 promotes the invasion, metastasis, and proliferation of pancreatic ductal adenocarcinoma via the PI3K/Akt/NF-κB pathway. Biochem Pharmacol 2024; 230:116580. [PMID: 39427920 DOI: 10.1016/j.bcp.2024.116580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/22/2024]
Abstract
Serpin peptidase inhibitor clade A member 1 (SERPINA1) is highly expressed in a variety of solid tumors. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we report evidence that SERPINA1 acts as a potent oncogene to drive its extremely malignant character. We found that elevated SERPINA1 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Mechanistic investigations revealed that overexpression of SERPINA1 induced nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, thereby promoting the invasion, metastasis and proliferation of PDAC cells in vitro and in vivo. Conversely, the knockdown of SERPINA1 attenuated this signaling pathway and restored the phenotype of PDAC cells overexpressing SERPINA1. Overall, our study reveals that SERPINA1 affects the properties of PDAC through the PI3K/Akt/NF-κB pathway, and its activation confers the clinical features of epithelial-mesenchymal transition and proliferation in the disease.
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Affiliation(s)
- Chen Xiubing
- Department of Gastroenterology, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Li Huazhen
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Wei Xueyan
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Ning Jing
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Li Qing
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Jiang Haixing
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Qin Shanyu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
| | - Lu Jiefu
- Department of Gastroenterology, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
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3
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Sun X, Wang S, Wong CC. Mass spectrometry–based proteomics technology in pancreatic cancer research. JOURNAL OF PANCREATOLOGY 2024; 7:145-163. [DOI: 10.1097/jp9.0000000000000152] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has become a significant health concern with increasing incidence and mortality rates over the past few decades. Researchers have turned their attention to cutting-edge mass spectrometry (MS) technology due to its high-throughput and accurate detection capacity, which plays a vital role in understanding the mechanisms and discovering biomarkers for pancreatic diseases. In this review, we comprehensively investigate various methodologies of quantitative and qualitative proteomics MS technologies, alongside bioinformatical platforms employed in pancreatic cancer research. The integration of these optimized approaches provides novel insights into the molecular mechanisms underlying tumorigenesis and disease progression, ultimately facilitating the discovery of potential diagnostic, prognostic biomarkers, and therapeutic targets. The robust MS-based strategy shows promise in paving the way for early diagnosis and personalized medicine for pancreatic cancer patients.
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Affiliation(s)
- Xue Sun
- First School of Clinical Medicine, Peking University Health Science Center, Peking University, Beijing 100871, China
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Siyuan Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
| | - Catherine C.L. Wong
- First School of Clinical Medicine, Peking University Health Science Center, Peking University, Beijing 100871, China
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
- Tsinghua-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China
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Bengtsson A, Draus T, Andersson R, Ansari D. Prediagnostic blood biomarkers for pancreatic cancer: meta-analysis. BJS Open 2024; 8:zrae046. [PMID: 38935426 PMCID: PMC11210304 DOI: 10.1093/bjsopen/zrae046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 02/27/2024] [Accepted: 04/04/2024] [Indexed: 06/28/2024] Open
Affiliation(s)
- Axel Bengtsson
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
| | - Tomasz Draus
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
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Silva MLS. Capitalizing glycomic changes for improved biomarker-based cancer diagnostics. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:366-395. [PMID: 37455827 PMCID: PMC10344901 DOI: 10.37349/etat.2023.00140] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/24/2023] [Indexed: 07/18/2023] Open
Abstract
Cancer serum biomarkers are valuable or even indispensable for cancer diagnostics and/or monitoring and, currently, many cancer serum markers are routinely used in the clinic. Most of those markers are glycoproteins, carrying cancer-specific glycan structures that can provide extra-information for cancer monitoring. Nonetheless, in the majority of cases, this differential feature is not exploited and the corresponding analytical assays detect only the protein amount, disregarding the analysis of the aberrant glycoform. Two exceptions to this trend are the biomarkers α-fetoprotein (AFP) and cancer antigen 19-9 (CA19-9), which are clinically monitored for their cancer-related glycan changes, and only the AFP assay includes quantification of both the protein amount and the altered glycoform. This narrative review demonstrates, through several examples, the advantages of the combined quantification of protein cancer biomarkers and the respective glycoform analysis, which enable to yield the maximum information and overcome the weaknesses of each individual analysis. This strategy allows to achieve higher sensitivity and specificity in the detection of cancer, enhancing the diagnostic power of biomarker-based cancer detection tests.
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Affiliation(s)
- Maria Luísa S. Silva
- Unidade de Aprendizagem ao Longo da Vida, Universidade Aberta, 1269-001 Lisboa, Portugal
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van der Burgt Y, Wuhrer M. The role of clinical glyco(proteo)mics in precision medicine. Mol Cell Proteomics 2023:100565. [PMID: 37169080 DOI: 10.1016/j.mcpro.2023.100565] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/12/2023] [Accepted: 05/02/2023] [Indexed: 05/13/2023] Open
Abstract
Glycoproteomics reveals site-specific O- and N-glycosylation that may influence protein properties including binding, activity and half-life. The increasingly mature toolbox with glycomic- and glycoproteomic strategies is applied for the development of biopharmaceuticals and discovery and clinical evaluation of glycobiomarkers in various disease fields. Notwithstanding the contributions of glycoscience in identifying new drug targets, the current report is focused on the biomarker modality that is of interest for diagnostic and monitoring purposes. To this end it is noted that the identification of biomarkers has received more attention than corresponding quantification. Most analytical methods are very efficient in detecting large numbers of analytes but developments to accurately quantify these have so far been limited. In this perspective a parallel is made with earlier proposed tiers for protein quantification using mass spectrometry. Moreover, the foreseen reporting of multimarker readouts is discussed to describe an individual's health or disease state and their role in clinical decision-making. The potential of longitudinal sampling and monitoring of glycomic features for diagnosis and treatment monitoring is emphasized. Finally, different strategies that address quantification of a multimarker panel will be discussed.
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Affiliation(s)
- Yuri van der Burgt
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
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Oh MJ, Lee SH, Kim U, An HJ. In-depth investigation of altered glycosylation in human haptoglobin associated cancer by mass spectrometry. MASS SPECTROMETRY REVIEWS 2023; 42:496-518. [PMID: 34037272 DOI: 10.1002/mas.21707] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/28/2021] [Accepted: 05/12/2021] [Indexed: 05/08/2023]
Abstract
Serum haptoglobin (Hp), a highly sialylated biomolecule with four N-glycosylation sites, is a positive acute-phase response glycoprotein that acts as an immunomodulator. Hp has gained considerable attention due to its potential as a signature molecule that exhibits aberrant glycosylation in inflammatory disorders and malignancies. Its glycosylation can be analyzed qualitatively and quantitatively by various methods using mass spectrometry. In this review, we have provided a brief overview of Hp structure and biological function and described mass spectrometry-based techniques for analyzing glycosylation ranging from macroheterogeneity to microheterogeneity of Hp in diseases and cancer. The sugars on haptoglobin can be a sweet bridge to link the potential of cancer-specific biomarkers to clinically relevant applications.
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Affiliation(s)
- Myung Jin Oh
- Asia-Pacific Glycomics Reference Site, Daejeon, South Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea
| | - Sung Hyeon Lee
- Department of Biomedical Research Center, Korea University Guro Hospital, Seoul, South Korea
| | - Unyoung Kim
- Division of Bioanalysis, Biocomplete Inc., Seoul, South Korea
| | - Hyun Joo An
- Asia-Pacific Glycomics Reference Site, Daejeon, South Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea
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8
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Levink IJM, Klatte DCF, Hanna-Sawires RG, Vreeker GCM, Ibrahim IS, van der Burgt YEM, Overbeek KA, Koopmann BDM, Cahen DL, Fuhler GM, Wuhrer M, Bonsing BA, Tollenaar RAEM, Vleggaar FP, Vasen HFA, van Leerdam ME, Bruno MJ, Mesker WE. Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals. Pancreatology 2022; 22:497-506. [PMID: 35414481 DOI: 10.1016/j.pan.2022.03.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 03/25/2022] [Accepted: 03/31/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. METHODS Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. RESULTS 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. CONCLUSION Serum N-glycan monitoring may support early detection in a pancreas surveillance program.
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Affiliation(s)
- I J M Levink
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
| | - D C F Klatte
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - R G Hanna-Sawires
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - G C M Vreeker
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - I S Ibrahim
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Y E M van der Burgt
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - K A Overbeek
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - B D M Koopmann
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - D L Cahen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - G M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - M Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - B A Bonsing
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - R A E M Tollenaar
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - F P Vleggaar
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - H F A Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - M E van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - M J Bruno
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - W E Mesker
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
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9
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Kumari M, Singh P, Singh N, Bal A, Srinivasan R, Ghosh S. Identification and characterization of non-small cell lung cancer associated sialoglycoproteins. J Proteomics 2021; 248:104336. [PMID: 34298184 DOI: 10.1016/j.jprot.2021.104336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 06/29/2021] [Accepted: 07/05/2021] [Indexed: 12/18/2022]
Abstract
Aberrantly sialylated cellular glycoconjugates were found to be involved in different processes during tumorigenesis. Such alteration was also noted in case of lung cancer, an important cause of cancer-related death throughout the world. Thus, study on lung cancer associated sialoglycoproteins is of paramount relevance to have a deeper insight into the mechanism of the disease pathogenesis. In the present study, sialic acid specific lectin (Maackia amurensis agglutinin and Sambcus nigra agglutinin)-based affinity chromatography followed by 2D-PAGE and MALDI-TOF/TOF mass spectrometric analysis were done to explore the disease-associated serum proteins of squamous cell carcinoma and adenocarcinoma [the major two subtypes of NSCLC (non-small cell lung carcinoma)] patients. Among seven identified proteins, α1-antitrypsin and haptoglobin-β were preferred for further studies. These two proteins were characterized as the disease associated serum-sialoglycoproteins of NSCLC-patients by western immunoblotting using each lectin specific inhibitor. The presence of these sialoglycoproteins was found on NSCLC cell lines (NCI-H520 & A549) by confocal microscopy. Both these proteins were also present in tissue samples of NSCLC origin and involved in proliferation, invasion and migration of NSCLC cells. Our findings suggest that α1-antitrypsin and haptoglobin-β may be the disease-associated sialoglycoproteins in NSCLC, which seem to be involved in disease progression. SIGNIFICANCE: Our contribution regarding the identification of the NSCLC associated sialoglycoproteins may provide a new vision towards the development of clinically useful newer strategies for the treatment of this disease.
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Affiliation(s)
- Munmun Kumari
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Praveen Singh
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Navneet Singh
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amanjit Bal
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Radhika Srinivasan
- Department of Cytology & Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sujata Ghosh
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Tabang DN, Ford M, Li L. Recent Advances in Mass Spectrometry-Based Glycomic and Glycoproteomic Studies of Pancreatic Diseases. Front Chem 2021; 9:707387. [PMID: 34368082 PMCID: PMC8342852 DOI: 10.3389/fchem.2021.707387] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Modification of proteins by glycans plays a crucial role in mediating biological functions in both healthy and diseased states. Mass spectrometry (MS) has emerged as the most powerful tool for glycomic and glycoproteomic analyses advancing knowledge of many diseases. Such diseases include those of the pancreas which affect millions of people each year. In this review, recent advances in pancreatic disease research facilitated by MS-based glycomic and glycoproteomic studies will be examined with a focus on diabetes and pancreatic cancer. The last decade, and especially the last five years, has witnessed developments in both discovering new glycan or glycoprotein biomarkers and analyzing the links between glycans and disease pathology through MS-based studies. The strength of MS lies in the specificity and sensitivity of liquid chromatography-electrospray ionization MS for measuring a wide range of biomolecules from limited sample amounts from many sample types, greatly enhancing and accelerating the biomarker discovery process. Furthermore, imaging MS of glycans enabled by matrix-assisted laser desorption/ionization has proven useful in complementing histology and immunohistochemistry to monitor pancreatic disease progression. Advances in biological understanding and analytical techniques, as well as challenges and future directions for the field, will be discussed.
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Affiliation(s)
- Dylan Nicholas Tabang
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, United States
| | - Megan Ford
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, United States
| | - Lingjun Li
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, United States.,School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States
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Benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers: a case study of pancreatic cancer. Glycoconj J 2021; 38:213-231. [PMID: 33835347 DOI: 10.1007/s10719-021-09994-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a highly malignant tumor of the digestive tract that is difficult to diagnose and treat. It is more common in developed countries and has become one of the main causes of death in some countries and regions. Currently, pancreatic cancer generally has a poor prognosis, partly due to the lack of symptoms in the early stages of pancreatic cancer. Therefore, most cases are diagnosed at advanced stage. With the continuous in-depth research of glycoproteomics in precision medical diagnosis, there have been some reports on quantitative analysis of cancer-related cells, plasma or tissues to find specific biomarkers for targeted therapy. This research is based on the developed complete N-linked glycopeptide database search engine GPSeeker, combined with liquid-mass spectrometry and stable diethyl isotope labeling, providing a benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers. With spectrum-level FDR ≤1%, 20,038 intact N-Glycopeptides corresponding to 4518 peptide backbones, 228 N-glycan monosaccharide compositions 1026 N-glycan putative structures, 4460 N-glycosites and 3437 intact N-glycoproteins were identified. With the criteria of ≥1.5-fold change and p value<0.05, 52 differentially expressed intact N-glycopeptides (DEGPs) were found in pancreatic cancer tussues relative to control, where 38 up-regulated and 14 down-regulated, respectively.
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12
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Li L, Wu J, Yang L, Wang H, Xu Y, Shen K. Fourier Transform Infrared Spectroscopy: An Innovative Method for the Diagnosis of Ovarian Cancer. Cancer Manag Res 2021; 13:2389-2399. [PMID: 33737836 PMCID: PMC7965685 DOI: 10.2147/cmar.s291906] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/03/2021] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is the most lethal gynecologic malignancy due to the late diagnoses at advanced stages, drug resistance and the high recurrence rate. Thus, there is an urgent need to develop new techniques to diagnose and monitor ovarian cancer patients. Fourier transform infrared (FTIR) spectroscopy has great potential in the diagnosis of this disease, as well as the real-time monitoring of cancer development and chemoresistance. As a noninvasive, simple and convenient technique, it can not only distinguish the molecular differences between normal and malignant tissues, but also be used to identify the characteristics of different types of ovarian cancer. FTIR spectroscopy is also widely used in monitoring cancer cells in response to antitumor drugs, distinguishing cells in different growth states, and identifying new synthetic drugs. In this paper, the applications of FTIR spectroscopy for ovarian cancer diagnosis and other works carried out so far are described in detail.
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Affiliation(s)
- Lei Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Jinguang Wu
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Rare Earth Materials Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing, People's Republic of China
| | - Limin Yang
- State Key Laboratory of Nuclear Physics and Technology, Institute of Heavy Ion Physics, School of Physics, Peking University, Beijing, People's Republic of China
| | - Huizi Wang
- Medical Science Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Yizhuang Xu
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Rare Earth Materials Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing, People's Republic of China
| | - Keng Shen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
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13
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Clinical Perspective on Proteomic and Glycomic Biomarkers for Diagnosis, Prognosis, and Prediction of Pancreatic Cancer. Int J Mol Sci 2021; 22:ijms22052655. [PMID: 33800786 PMCID: PMC7961509 DOI: 10.3390/ijms22052655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical techniques and new (neo)adjuvant chemotherapy regimens. Early detection of PDAC may increase the overall survival. It is furthermore foreseen that precision medicine will provide improved prognostic stratification and prediction of therapeutic response. In this review, omics-based discovery efforts are presented that aim for novel diagnostic and prognostic biomarkers of PDAC. For this purpose, we systematically evaluated the literature published between 1999 and 2020 with a focus on protein- and protein-glycosylation biomarkers in pancreatic cancer patients. Besides genomic and transcriptomic approaches, mass spectrometry (MS)-based proteomics and glycomics of blood- and tissue-derived samples from PDAC patients have yielded new candidates with biomarker potential. However, for reasons discussed in this review, the validation and clinical translation of these candidate markers has not been successful. Consequently, there has been a change of mindset from initial efforts to identify new unimarkers into the current hypothesis that a combination of biomarkers better suits a diagnostic or prognostic panel. With continuing development of current research methods and available techniques combined with careful study designs, new biomarkers could contribute to improved detection, prognosis, and prediction of pancreatic cancer.
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14
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Vreeker GCM, Hanna-Sawires RG, Mohammed Y, Bladergroen MR, Nicolardi S, Dotz V, Nouta J, Bonsing BA, Mesker WE, van der Burgt YEM, Wuhrer M, Tollenaar RAEM. Serum N-Glycome analysis reveals pancreatic cancer disease signatures. Cancer Med 2020; 9:8519-8529. [PMID: 32898301 PMCID: PMC7666731 DOI: 10.1002/cam4.3439] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 07/08/2020] [Accepted: 08/16/2020] [Indexed: 12/13/2022] Open
Abstract
Background &Aims Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with loco‐regional spread that makes the tumor surgically unresectable. Novel diagnostic tools are needed to improve detection of PDAC and increase patient survival. In this study we explore serum protein N‐glycan profiles from PDAC patients with regard to their applicability to serve as a disease biomarker panel. Methods Total serum N‐glycome analysis was applied to a discovery set (86 PDAC cases/84 controls) followed by independent validation (26 cases/26 controls) using in‐house collected serum specimens. Protein N‐glycan profiles were obtained using ultrahigh resolution mass spectrometry and included linkage‐specific sialic acid information. N‐glycans were relatively quantified and case‐control classification performance was evaluated based on glycosylation traits such as branching, fucosylation, and sialylation. Results In PDAC patients a higher level of branching (OR 6.19, P‐value 9.21 × 10−11) and (antenna)fucosylation (OR 13.27, P‐value 2.31 × 10−9) of N‐glycans was found. Furthermore, the ratio of α2,6‐ vs α2,3‐linked sialylation was higher in patients compared to healthy controls. A classification model built with three glycosylation traits was used for discovery (AUC 0.88) and independent validation (AUC 0.81), with sensitivity and specificity values of 0.85 and 0.71 for the discovery set and 0.75 and 0.72 for the validation set. Conclusion Serum N‐glycome analysis revealed glycosylation differences that allow classification of PDAC patients from healthy controls. It was demonstrated that glycosylation traits rather than single N‐glycan structures obtained in this clinical glycomics study can serve as a basis for further development of a blood‐based diagnostic test.
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Affiliation(s)
- Gerda C M Vreeker
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Yassene Mohammed
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Marco R Bladergroen
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Simone Nicolardi
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Viktoria Dotz
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan Nouta
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Bert A Bonsing
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Wilma E Mesker
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Yuri E M van der Burgt
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Rob A E M Tollenaar
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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15
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Huang P, Huang Z, Lu X, Cao Y, Yu J, Hou D, Zhang G. Study on glycoprotein terahertz time-domain spectroscopy based on composite multiscale entropy feature extraction method. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2020; 229:117948. [PMID: 31887681 DOI: 10.1016/j.saa.2019.117948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/02/2019] [Accepted: 12/10/2019] [Indexed: 05/05/2023]
Abstract
Tumor genesis is accompanied by glycosylation of related proteins. Glycoprotein is usually regarded as a tumor marker since glycoproteins are consumed remarkably more by the cancer cells than the normal ones. In this paper, the terahertz time-domain attenuated total reflection (ATR) technique is applied to inspect the glycoprotein solution from a concentration gradient of 0.2 mg/ml to 50 mg/ml. A significant nonlinear relationship between the absorption coefficient and the concentrations has been discovered. The influence of the dynamical hydration shell around glycoprotein molecules on the absorption coefficient is discussed and the phenomenon is explained by the concepts of THz excess and THz defect. In order to identify glycoproteins, features are obtained by composite multiscale entropy (CMSE) method and clustered by the K-means algorithm. The results indicate that features extracted by the CMSE method are better than the Principal Component Analysis (PCA) method in both specificity and sensitivity of recognition. Meanwhile, the absorption coefficient and dielectric loss angle tangent are more suitable for qualitative identification. Research shows that the CMSE method has important directive significance for analyzing glycoprotein terahertz spectroscopy. And it has the potential for glycoprotein related tumor markers identification using terahertz technology in medical applications.
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Affiliation(s)
- Pingjie Huang
- State Key Laboratory of Industrial Control Technology, College of Control Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China.
| | - Zhangwei Huang
- State Key Laboratory of Industrial Control Technology, College of Control Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China
| | - Xiaodong Lu
- State Key Laboratory of Industrial Control Technology, College of Control Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China
| | - Yuqi Cao
- State Key Laboratory of Industrial Control Technology, College of Control Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China
| | - Jie Yu
- State Key Laboratory of Industrial Control Technology, College of Control Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China
| | - Dibo Hou
- State Key Laboratory of Industrial Control Technology, College of Control Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China
| | - Guangxin Zhang
- State Key Laboratory of Industrial Control Technology, College of Control Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China.
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16
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Elek Z, Kovács Z, Keszler G, Szabó M, Csanky E, Luo J, Guttman A, Rónai Z. High Throughput Multiplex SNP-analysis in Chronic Obstructive Pulmonary Disease and Lung Cancer. Curr Mol Med 2020; 20:185-193. [DOI: 10.2174/1566524019666191017123446] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/11/2019] [Accepted: 10/11/2019] [Indexed: 01/01/2023]
Abstract
Background:
A number of human inflammatory diseases and tumors have
been shown to cause alterations in the glycosylation pattern of plasma proteins in a specific
manner. These highly variable and versatile post-translational modifications finetune
protein functions by influencing sorting, folding, enzyme activity and subcellular
localization. However, relatively little is known about regulatory factors of this procedure
and about the accurate causative connection between glycosylation and disease.
Objective:
The aim of the present study was to investigate whether certain single nucleotide
polymorphisms (SNPs) in genes encoding glycosyltransferases and glycosidases
could be associated with elevated risk for chronic obstructive pulmonary disease
(COPD) and lung adenocarcinoma.
Methods:
A total of 32 SNPs localized in genes related to N-glycosylation were selected
for the association analysis. Polymorphisms with putative biological functions (missense
or regulatory variants) were recruited. SNPs were genotyped by a TaqMan OpenArray
platform. A single base extension-based method in combination with capillary gel electrophoresis
was used for verification.
Results:
The TaqMan OpenArray approach provided accurate and reliable genotype
data (global call rate: 94.9%, accuracy: 99.6%). No significant discrepancy was detected
between the obtained and expected genotype frequency values (Hardy–Weinberg equilibrium)
in the healthy control sample group in case of any SNP confirming reliable sampling
and genotyping. Allele frequencies of the rs3944508 polymorphism localized in the
3’ UTR of the MGAT5 gene significantly differed between the sample groups compared.
Conclusion:
Our results suggest that the rs34944508 SNP might modulate the risk for
lung cancer by influencing the expression of MGAT5. This enzyme catalyzes the addition
of N-acetylglucosamine (GlcNAc) in beta 1-6 linkage to the alpha-linked mannose of
biantennary N-linked oligosaccharides, thus, increasing branching that is the characteristic
of invasive malignancies.
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Affiliation(s)
- Zsuzsanna Elek
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
| | - Zsuzsanna Kovács
- Horvath Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Doctoral School of Molecular Medicine, Faculty of Medicine, University of Debrecen, 98 Nagyerdei krt., Debrecen, 4032, Hungary
| | - Gergely Keszler
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
| | | | | | - Jane Luo
- SCIEX Separations, Brea, CA 92821, United States
| | | | - Zsolt Rónai
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
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17
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Wang M, Zhu J, Lubman DM, Gao C. Aberrant glycosylation and cancer biomarker discovery: a promising and thorny journey. Clin Chem Lab Med 2019; 57:407-416. [PMID: 30138110 PMCID: PMC6785348 DOI: 10.1515/cclm-2018-0379] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 07/15/2018] [Indexed: 12/12/2022]
Abstract
Glycosylation is among the most important post-translational modifications for proteins and is of intrinsic complex character compared with DNAs and naked proteins. Indeed, over 50%-70% of proteins in circulation are glycosylated, and the "sweet attachments" have versatile structural and functional implications. Both the configuration and composition of the attached glycans affect the biological activities of consensus proteins significantly. Glycosylation is generated by complex biosynthetic pathways comprising hundreds of glycosyltransferases, glycosidases, transcriptional factors, transporters and the protein backbone. In addition, lack of direct genetic templates and glyco-specific antibodies such as those commonly used in DNA amplification and protein capture makes research on glycans and glycoproteins even more difficult, thus resulting in sparse knowledge on the pathophysiological implications of glycosylation. Fortunately, cutting-edge technologies have afforded new opportunities and approaches for investigating cancer-related glycosylation. Thus, glycans as well as aberrantly glycosylated protein-based cancer biomarkers have been increasingly recognized. This mini-review highlights the most recent developments in glyco-biomarker studies in an effort to discover clinically relevant cancer biomarkers using advanced analytical methodologies such as mass spectrometry, high-performance liquid chromatographic/ultra-performance liquid chromatography, capillary electrophoresis, and lectin-based technologies. Recent clinical-centered glycobiological studies focused on determining the regulatory mechanisms and the relation with diagnostics, prognostics and even therapeutics are also summarized. These studies indicate that glycomics is a treasure waiting to be mined where the growth of cancer-related glycomics and glycoproteomics is the next great challenge after genomics and proteomics.
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Affiliation(s)
- Mengmeng Wang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - David M. Lubman
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Chunfang Gao
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, P.R. China
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18
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Mancera-Arteu M, Giménez E, Balmaña M, Barrabés S, Albiol-Quer M, Fort E, Peracaula R, Sanz-Nebot V. Multivariate data analysis for the detection of human alpha-acid glycoprotein aberrant glycosylation in pancreatic ductal adenocarcinoma. J Proteomics 2019; 195:76-87. [PMID: 30641231 DOI: 10.1016/j.jprot.2019.01.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 12/24/2018] [Accepted: 01/07/2019] [Indexed: 12/27/2022]
Abstract
Relative quantification of human alpha-acid glycoprotein (hAGP) glycan isomers using [12C6]/[13C6]-aniline in combination with multivariate data analysis is proposed as an efficient method for the identification of pancreatic ductal adenocarcinoma (PDAC) glycan biomarkers in serum samples. Intact and desialylated glycans from hAGP, purified from serum samples of patients with PDAC and chronic pancreatitis (ChrP), were labeled with aniline and analyzed by μZIC-HILIC-MS. Afterwards, partial least squares discriminant analysis (PLS-DA) was applied to the relative areas obtained for all glycan isomers in the different samples: pathological (ChrP or PDAC) versus healthy samples. Seven intact glycan isomers with α2-6 linked sialic acids, five of them also fucosylated, were the most meaningful to distinguish between PDAC and ChrP patients. The desialylated glycan isomers also identified by PLS-DA as potential biomarker candidates confirmed that antenna but also core fucosylation could be involved in PDAC. The analysis of intact and desialylated glycan isomers in combination with the multivariate data analysis revealed that the triantennary glycan with two fucoses of hAGP could have in the future a relevant role in the differentiation of patients with PDAC from those with ChrP. SIGNIFICANCE: Multivariate data analysis is currently being used in many omics fields for biomarker discovery. However, to date, no glycomics studies have applied chemometric tools combined with mass spectrometry in a preclinical research. In this work, this methodology has been used to identify altered glycosylation of human alpha-acid glycoprotein in pancreatic ductal adenocarcinoma (PDAC). The obtained results reveal that the triantennary glycan with two fucoses could have a great biomarker potential as it was relevant to differentiate PDAC and chronic pancreatitis (ChrP) patients.
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Affiliation(s)
- Montserrat Mancera-Arteu
- Department of Chemical Engineering and Analytical Chemistry, Institute for Research on Nutrition and Food Safety (INSA·UB), University of Barcelona, Barcelona, Spain
| | - Estela Giménez
- Department of Chemical Engineering and Analytical Chemistry, Institute for Research on Nutrition and Food Safety (INSA·UB), University of Barcelona, Barcelona, Spain.
| | - Meritxell Balmaña
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain; Glycobiology in Cancer Group, i3S - Instituto de Investigação e Inovação em Saúde, Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Sílvia Barrabés
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain; Biomedical Research Institute of Girona (IdIBGi), Salt, Spain
| | - Maite Albiol-Quer
- Department of Surgery, Dr. Josep Trueta University Hospital, Girona, Spain
| | - Esther Fort
- Department of Gastroenterology, Dr. Josep Trueta University Hospital, Girona, Spain
| | - Rosa Peracaula
- Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain; Biomedical Research Institute of Girona (IdIBGi), Salt, Spain
| | - Victòria Sanz-Nebot
- Department of Chemical Engineering and Analytical Chemistry, Institute for Research on Nutrition and Food Safety (INSA·UB), University of Barcelona, Barcelona, Spain
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19
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Aronsson L, Andersson R, Bauden M, Andersson B, Bygott T, Ansari D. High-density and targeted glycoproteomic profiling of serum proteins in pancreatic cancer and intraductal papillary mucinous neoplasm. Scand J Gastroenterol 2018; 53:1597-1603. [PMID: 30509115 DOI: 10.1080/00365521.2018.1532020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/29/2018] [Accepted: 09/29/2018] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Glycoproteomics is an emerging subfield of proteomics. Tumor-specific variations in protein glycosylation might be potential targets for the development of new cancer diagnostics. Here, we performed high-throughput screening and targeted verification of glycome alterations in serum samples from patients with pancreatic cancer and the precancerous lesion intraductal papillary mucinous neoplasm (IPMN). MATERIAL AND METHODS The glycosylation profile of 1000 proteins was mapped in a discovery cohort comprising serum samples from 16 individuals, including 8 patients with pancreatic cancer and 8 healthy controls. The top 10 glycoprotein biomarker candidates with the highest signal intensity difference in glycosylation levels were evaluated in a cohort consisting of 109 serum samples, including 49 patients with resectable pancreatic cancer, 13 patients with resectable noninvasive IPMN and 47 healthy controls, using a targeted assay. RESULTS Multivariable analysis defined sets of panels comprising CA19-9 and distinctively glycosylated proteins for discrimination between pancreatic cancer, IPMN and healthy controls. A panel including CA 19-9, IL.17E, B7.1 and DR6 gave an AUC of 0.988 at 100% sensitivity at 90% specificity for the discrimination of stage 1 pancreatic cancer and healthy controls. B7.1 was found to be a valuable biomarker for differentiating between IPMN and healthy controls, with better performance alone than CA 19-9. CONCLUSIONS Measurement of protein glycosylation profiles in serum may aid in the early detection of pancreatic cancer and precursor lesions.
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Affiliation(s)
- Linus Aronsson
- a Department of Surgery, Clinical Sciences Lund , Skåne University Hospital, Lund University , Lund , Sweden
| | - Roland Andersson
- a Department of Surgery, Clinical Sciences Lund , Skåne University Hospital, Lund University , Lund , Sweden
| | - Monika Bauden
- a Department of Surgery, Clinical Sciences Lund , Skåne University Hospital, Lund University , Lund , Sweden
| | - Bodil Andersson
- a Department of Surgery, Clinical Sciences Lund , Skåne University Hospital, Lund University , Lund , Sweden
| | | | - Daniel Ansari
- a Department of Surgery, Clinical Sciences Lund , Skåne University Hospital, Lund University , Lund , Sweden
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20
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Gabriele C, Cantiello F, Nicastri A, Crocerossa F, Russo GI, Cicione A, Vartolomei MD, Ferro M, Morgia G, Lucarelli G, Cuda G, Damiano R, Gaspari M. High-throughput detection of low abundance sialylated glycoproteins in human serum by TiO 2 enrichment and targeted LC-MS/MS analysis: application to a prostate cancer sample set. Anal Bioanal Chem 2018; 411:755-763. [PMID: 30483857 DOI: 10.1007/s00216-018-1497-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/03/2018] [Accepted: 11/13/2018] [Indexed: 12/22/2022]
Abstract
Glycopeptide enrichment can be a strategy to allow the detection of peptides belonging to low abundance proteins in complex matrixes such as blood serum or plasma. Though several glycopeptide enrichment protocols have shown excellent sensitivities in this respect, few reports have demonstrated the applicability of these methods to relatively large sample cohorts. In this work, a fast protocol based on TiO2 enrichment and highly sensitive mass spectrometric analysis by Selected Reaction Monitoring (SRM) has been applied to a cohort of serum samples from prostate cancer and benign prostatic hyperplasia patients in order to detect low abundance proteins in a single LC-MS/MS analysis in nanoscale format, without immunodepletion or peptide fractionation. A peptide library of over 700 formerly N-glycosylated peptides was created by data dependent analysis. Then, 16 medium to low abundance proteins were selected for detection by single injection LC-MS/MS based on selected-reaction monitoring. Results demonstrated the consistent detection of the low-level proteins under investigation. Following label-free quantification, four proteins (Adipocyte plasma membrane-associated protein, Periostin, Cathepsin D and Lysosome-associated membrane glycoprotein 2) were found significantly increased in prostate cancer sera compared to the control group. Graphical abstract ᅟ.
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Affiliation(s)
- Caterina Gabriele
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy
| | - Francesco Cantiello
- Urology Unit, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy.
| | - Annalisa Nicastri
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy
| | - Fabio Crocerossa
- Urology Unit, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy
| | - Giorgio Ivan Russo
- Urology Section, Department of Surgery, University of Catania, 95131, Catania, Italy
| | - Antonio Cicione
- Urology Unit, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy
| | - Mihai D Vartolomei
- Department of Urology, European Institute of Oncology, 20141, Milan, Italy.,Department of Cell and Molecular Biology, University of Medicine, Pharmacy, Sciences and Technology, 540139, Targu Mures, Romania
| | - Matteo Ferro
- Department of Urology, European Institute of Oncology, 20141, Milan, Italy
| | - Giuseppe Morgia
- Urology Section, Department of Surgery, University of Catania, 95131, Catania, Italy
| | - Giuseppe Lucarelli
- Urology, Andrology & Kidney Transplantation Unit, Department of Emergency & Organ Transplantation, University of Bari, 70121, Bari, Italy
| | - Giovanni Cuda
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy
| | - Rocco Damiano
- Urology Unit, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy
| | - Marco Gaspari
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Campus "S. Venuta", Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy.
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21
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Waldron RT, Lugea A, Gulla A, Pandol SJ. Proteomic Identification of Novel Plasma Biomarkers and Pathobiologic Pathways in Alcoholic Acute Pancreatitis. Front Physiol 2018; 9:1215. [PMID: 30214418 PMCID: PMC6125332 DOI: 10.3389/fphys.2018.01215] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 08/13/2018] [Indexed: 12/12/2022] Open
Abstract
Acute pancreatitis (AP) is a painful and potentially life-threatening disorder with the potential for therapeutic interventions. Biomarkers that characterize cases by severity and pathogenic mechanisms involved are not yet available but needed for the implementation of rational therapies. Here, we used shotgun proteomics to obtain information from plasma samples about local and systemic pathologies taking place during cases of alcoholic AP. Plasma was obtained at Kaunas University of Medicine Hospital (Lithuania) from 12 AP patients of alcohol related etiology (median age of 40) within 24 h of presentation, and 12 age-matched, healthy controls. Patients entered into the study had moderately severe AP with the following characteristics: mean blood lactate dehydrogenase level of 1127 mg/dl; median APACHEII score of 5.5 and mean IMRIE score of 3.5. For proteomic analysis, less-abundant proteins in plasma samples were enriched using Top 12 abundant protein depletion columns. Further processing was performed by a modified filter-assisted sample preparation combined with tandem mass tag labeling for quantitation. Samples were analyzed using an Orbitrap Elite mass spectrometer for high resolution liquid chromatography–tandem mass spectrometry (LC–MS/MS). Our analysis revealed 31 proteins that exhibited significant 1.5-fold or higher increases in the AP compared to control patients, and six that were significantly decreased. Gene ontology analysis indicated a strong correlation with exosomal origin in the elevated proteins, with 29/31 (93.5%) associated with this extracellularly-secreted compartment. Elevated proteins included established and proposed biomarkers of AP including C-reactive protein, LPS-binding protein, intercellular adhesion molecule-1, and von Willebrand factor, as well as several novel potential biomarkers. These results provide the methodology for proteomic analysis of plasma samples to discover novel biomarkers that characterize pancreatitis cases by pathogenic mechanism as well as disease activity at an early stage that is highly informative for routine clinical practice and clinical trials.
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Affiliation(s)
- Richard T Waldron
- Pancreatic Research Group, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Aurelia Lugea
- Pancreatic Research Group, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Aiste Gulla
- Department of Surgery, Georgetown University Hospital, Washington, DC, United States.,Department of Surgery, Vilnius University Hospital Santaros Clinics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Stephen J Pandol
- Pancreatic Research Group, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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22
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Llop E, Guerrero PE, Duran A, Barrabés S, Massaguer A, Ferri MJ, Albiol-Quer M, de Llorens R, Peracaula R. Glycoprotein biomarkers for the detection of pancreatic ductal adenocarcinoma. World J Gastroenterol 2018; 24:2537-2554. [PMID: 29962812 PMCID: PMC6021768 DOI: 10.3748/wjg.v24.i24.2537] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/04/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaC) shows a clear tendency to increase in the next years and therefore represents an important health and social challenge. Currently, there is an important need to find biomarkers for PaC early detection because the existing ones are not useful for that purpose. Recent studies have indicated that there is a large window of time for PaC early detection, which opens the possibility to find early biomarkers that could greatly improve the dismal prognosis of this tumor. The present manuscript reviews the state of the art of the existing PaC biomarkers. It focuses on the anomalous glycosylation process and its role in PaC. Glycan structures of glycoconjugates such as glycoproteins are modified in tumors and these modifications can be detected in biological fluids of the cancer patients. Several studies have found serum glycoproteins with altered glycan chains in PaC patients, but they have not shown enough specificity for PaC. To find more specific cancer glycoproteins we propose to analyze the glycan moieties of a battery of glycoproteins that have been reported to increase in PaC tissues and that can also be found in serum. The combination of these new candidate glycoproteins with their aberrant glycosylation together with the existing biomarkers could result in a panel, which would expect to give better results as a new tool for early diagnosis of PaC and to monitor the disease.
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Affiliation(s)
- Esther Llop
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Pedro E Guerrero
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Adrià Duran
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Sílvia Barrabés
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Anna Massaguer
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - María José Ferri
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
- Clinic Laboratory, University Hospital Dr Josep Trueta, Girona 17007, Spain
| | - Maite Albiol-Quer
- Department of Surgery, Hepato-biliary and Pancreatic Surgery Unit, University Hospital Dr Josep Trueta, Girona 17007, Spain
| | - Rafael de Llorens
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Rosa Peracaula
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
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Outstanding female cancer research paper awards of the Taiwanese Association of Obstetrics and Gynecology. Taiwan J Obstet Gynecol 2018. [DOI: 10.1016/j.tjog.2018.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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