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Ge W, Wen S, Zhou X, Chen Y, Zeng D, Jiang J, Yang S. FOXA2 Loss in TGF-β1-Induced EMT Suppresses Bisecting-GlcNAc N-Glycan Synthesis in Lung Adenocarcinoma. Proteomics 2025; 25:e202400216. [PMID: 40051143 DOI: 10.1002/pmic.202400216] [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: 06/21/2024] [Revised: 12/12/2024] [Accepted: 02/18/2025] [Indexed: 04/25/2025]
Abstract
Glycosylation, a major posttranslational modification (PTM), is often dysregulated in cancer due to altered glycosyltransferase activity. Studies have shown specific changes in glycan structures associated with epithelial-mesenchymal transition (EMT) in cancer cells. However, the specific mechanism by which glycosyltransferases contribute to EMT remains unclear. In this study, we used bronchoalveolar lavage fluid (BALF) from lung adenocarcinoma (LUAD) patients to comparatively characterize glycopatterns and identify dysregulated glycosyltransferases in LUAD. We found a significant reduction in N-glycans containing the bisecting GlcNAc structure and confirmed by Western blot that N-acetylglucosaminyltransferase-III (MGAT3) is downregulated in LUAD. We observed a notable downregulation of both messenger RNA (mRNA) and protein expression of Forkhead box protein A2 (FOXA2) in early-stage LUAD, with FOXA2 loss emerging as an EMT promoter. Interestingly, cellular EMT models demonstrated that FOXA2 deficiency decreased MGAT3 expression during TGF-β1-driven EMT, leading to reduced levels of bisecting-GlcNAc N-glycans in LUAD cells. Our findings unveil a novel mechanism underlying the downregulation of MGAT3 and bisecting GlcNAc N-glycan expression during EMT, a process crucial for tumor metastasis.
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Affiliation(s)
- Wei Ge
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Shengye Wen
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics, and Therapeutics Development, Suzhou, Jiangsu, China
| | - Xiaoli Zhou
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yan Chen
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics, and Therapeutics Development, Suzhou, Jiangsu, China
| | - Daxiong Zeng
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Junhong Jiang
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Shuang Yang
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics, and Therapeutics Development, Suzhou, Jiangsu, China
- Health Examination Center, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Zhang Y, Cui K, Qiang R, Wang L. FUT10 is related to the poor prognosis and immune infiltration in clear cell renal cell carcinoma. Transl Cancer Res 2025; 14:827-842. [PMID: 40104704 PMCID: PMC11912032 DOI: 10.21037/tcr-24-449] [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: 03/19/2024] [Accepted: 11/21/2024] [Indexed: 03/20/2025]
Abstract
Background Clear cell renal cell carcinoma (ccRCC), is highly metastatic with unfavorable oncologic outcomes. The metastatic dissemination and underlying mechanisms of ccRCC remain insufficiently understood. The expression of fucosyltransferases (FUTs) has been explored in multiple cancer types, which affect survival of tumor cells and oncology progress. However, the role of fucosyltransferase 10 (FUT10), a member of the FUT family, is still unclear in ccRCC. We aimed to investigate the effects of FUT10 on the prognosis and immune infiltration of ccRCC via The Cancer Genome Atlas (TCGA) database. Methods The relationship between FUT10 expression and clinical-pathologic features was evaluated by Welch's t-test, Wilcoxon signed-rank test, Dunn's test, and logistic regression based on TCGA datasets. The FUT10 expression level was converted into a categorical variable by receiver operating characteristic (ROC) and the area under the curve (AUC). The factors associated with the prognosis were determined by Kaplan-Meier method. The function of FUT10 was identified by functional enrichment analysis, gene set enrichment analysis (GSEA), gene correlation analysis, and immune infiltration analysis. At last, we verified the FUT10 messenger RNA (mRNA) expression in ccRCC and adjacent kidney tissues by quantitative real-time polymerase chain reaction (qRT-PCR). Results Downregulated FUT10 expression in ccRCC was associated with the clinical stage (P<0.001), T stage (P<0.001), M stage (P<0.001), and overall survival (OS) event (P<0.001). The ROC curve suggested that FUT10 had a certain accuracy in the diagnostic ability in ccRCC (AUC =0.787). It was shown that patient survival was prolonged in the FUT10 high-expression group. Meanwhile, multivariate analysis displayed that FUT10 was an independent risk factor for ccRCC patients (P=0.003). Moreover, we uncovered that FUT10 was involved in the phenotype of the immune response, oxidative phosphorylation (OXPHOS), arachidonic acid (AA) metabolism, and primary immunodeficiency (PID) by function enrichment analysis and GSEA. In addition, in the high FUT10 expression group, natural killer (NK) CD56bright cells exhibited lower enrichment scores, and central memory T cells exhibited higher enrichment scores. Especially, ARL8B, a key factor in NK-mediated cytotoxicity, had a certain correlation with FUT10 (r=0.590, P<0.001). Compared to the normal kidney tissues, the FUT10 mRNA expression in the ccRCC was decreased (P=0.004). Conclusions FUT10 might be a promising immune therapy target and prognostic biomarker in ccRCC.
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Affiliation(s)
- Yuqi Zhang
- Center of Medical Genetics, Northwest Women's and Children's Hospital, Xi'an, China
| | - Ke Cui
- Center of Medical Genetics, Northwest Women's and Children's Hospital, Xi'an, China
| | - Rong Qiang
- Center of Medical Genetics, Northwest Women's and Children's Hospital, Xi'an, China
| | - Lin Wang
- Center of Medical Genetics, Northwest Women's and Children's Hospital, Xi'an, China
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Sintusen P, Vaeteewoottacharn K, Cha'on U, Pairojkul C, Aphivatanasiri C, Suttiprapa S, Mahalapbutr P, Silsirivanit A, Wongkham S, Luang S. Clinical impacts of Artocarpus lakoocha agglutinin-binding glycans for prognosis and treatment of cholangiocarcinoma. Sci Rep 2025; 15:436. [PMID: 39747977 PMCID: PMC11696817 DOI: 10.1038/s41598-024-84444-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025] Open
Abstract
Artocarpus lakoocha agglutinin (ALA), which specifically targets the Gal/GalNAc components of complex glycans, was isolated from the seeds of Artocarpus lakoocha. This study is the first to explore the role of ALA in identifying aberrant glycans, designated ALA-binding glycans (ALAG), and its implications in cholangiocarcinoma (CCA). ALA-histochemistry was used to evaluate ALAG expression in liver fluke-induced CCA tissues from hamsters (n = 60). Elevated ALAG expression was observed in hyperplastic ducts and significantly increased in CCA tissues, while normal biliary epithelium and hepatocytes showed no expression. Similar results were found in patient CCA tissues (n = 68), where higher ALAG levels correlated with shorter survival rates, indicating the involvement of ALAG in CCA development and progression. Furthermore, ALA treatment inhibited cell viability in CCA cell lines, as demonstrated by MTT and colony formation assays, and Ki-67 expression. ALA treatment also decreased cell migration and invasion, as shown by Transwell assays. Gelatin zymography suggested that these effects might be associated with reduced MMP-9 activity. Overall, these findings may position ALAG as a potential marker for poor prognosis in CCA, while ALA may serve as a novel lectin for both detection and therapeutic applications in CCA.
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Affiliation(s)
- Phisit Sintusen
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Ubon Cha'on
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chaiwat Aphivatanasiri
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sutas Suttiprapa
- Department of Tropical Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Panupong Mahalapbutr
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Atit Silsirivanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sukanya Luang
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
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Sun Y, Zhang W, Cong Q, Ge Y, Zhang J, Wang H, Wang Z, Wang Z. Overexpression of Glycosyltransferase 8 Domain Containing 1 Promotes Gastric Cancer Proliferation and Inhibits Apoptosis via Mediating PTPN6/JAK2/STAT3 Signaling Axis. Int J Med Sci 2024; 21:2943-2958. [PMID: 39628694 PMCID: PMC11610327 DOI: 10.7150/ijms.102719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/17/2024] [Indexed: 12/06/2024] Open
Abstract
Background: The mechanisms of gastric cancer (GC) occurrence and development are still unclear. Although glycosyltransferase 8 domain containing 1 (GLT8D1) has been implicated in GC, its specific role and molecular mechanisms in GC progression need to be further investigated. Methods: Tissue microarrays were used to detect the expression levels of GLT8D1 in 80 GC tissues and their corresponding non-tumor adjacent tissues. The correlations between the GLT8D1 expression level and clinicopathological characteristics were evaluated. A series of in vitro and in vivo functional experiments were performed to explore the role of GLT8D1 in GC progression. Combined with transcriptomic RNA sequencing (RNA-seq) and Weighted Gene Co-expression Network Analysis (WGCNA), we delineated the potential mechanisms via experimental verification. Results: Elevated expression of GLT8D1 in GC tissues was positively correlated with advanced clinical stages and poor prognosis. Konckdown of GLT8D1 significantly inhibited GC cell proliferation and induced apoptosis, whereas overexpression did the opposite. Further researches demonstrated that protein tyrosine phosphatase non-receptor type 6 (PTPN6), a downstream target of GLT8D1, has the capacity to modulate the activity of the JAK2/STAT3 signaling pathway. Conclusions: Our study indicated that GLT8D1 expression was upregulated in GC tissues and correlated with poor prognosis. We reveal a potential molecular mechanism by which GLT8D1 promotes GC progression.
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Affiliation(s)
- Yingying Sun
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Wuqian Zhang
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Qunyou Cong
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Yanli Ge
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Junjie Zhang
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Haiyang Wang
- Department of Laboratory Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Zhe Wang
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Zhirong Wang
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
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Zhao S, Sun J, Chang Q, Pang S, Zhang N, Fan Y, Liu J. CTCF-activated FUCA1 functions as a tumor suppressor by promoting autophagy flux and serum α-L-fucosidase serves as a potential biomarker for prognosis in ccRCC. Cancer Cell Int 2024; 24:327. [PMID: 39342260 PMCID: PMC11439243 DOI: 10.1186/s12935-024-03502-2] [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: 04/28/2024] [Accepted: 09/05/2024] [Indexed: 10/01/2024] Open
Abstract
Notably, clear cell renal cell carcinoma (ccRCC) is characterized by a distinct metabolic tumor phenotype that involves the reprogramming of multiple metabolic pathways. Although there is increasing evidence linking FUCA1 to malignancies, its specific role and downstream signaling pathways in ccRCC remain poorly understood. Here we found that FUCA1 expression was significantly downregulated in ccRCC tissues, which also predicts poor prognosis of ccRCCpatients. Moreover, enhancing FUCA1 expression resulted in reduced invasion and migration of ccRCC cells, further indicating its protective role. CHIP-qPCR and luciferase assays showed that CTCF was an upstream transcription factor of FUCA1 and could reverse the effects caused by FUCA1 inactivation. The change in FUCA1 led to changes in the results of various autophagy-related proteins and the mRFP-GFP-LC3 dual fluorescence system, indicating that it may play a role in the fusion stage of autophagy. Protein-protein interaction analysis revealed that FUCA2 exhibited the closest interaction with FUCA1 and strongly predicted the prognosis of ccRCC patients. Additionally, serum AFU encoded by FUCA2 could serve as a valuable predictor for survival in ccRCC patients. FUCA1 suppresses invasion and migration of ccRCC cells, with its activity being modulated by CTCF. FUCA1 regulates the autophagy process in ccRCC cells by influencing the fusion between autophagosomes and lysosomes. FUCA2 shares similarities with FUCA1, and elevated serum AFU levels along with increased expression of FUCA2 are indicative of a favorable prognosis in ccRCC.
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Affiliation(s)
- Shuo Zhao
- Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road Jinan, Jinan, Shandong, 250012, China
| | - Jiajia Sun
- Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road Jinan, Jinan, Shandong, 250012, China
| | - Qinzheng Chang
- Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road Jinan, Jinan, Shandong, 250012, China
| | - Shuo Pang
- Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road Jinan, Jinan, Shandong, 250012, China
| | - Nianzhao Zhang
- Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road Jinan, Jinan, Shandong, 250012, China
| | - Yidong Fan
- Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road Jinan, Jinan, Shandong, 250012, China.
| | - Jikai Liu
- Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road Jinan, Jinan, Shandong, 250012, China.
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Obiako PC, Ayisire SO, Sayes CM. Impact of perfluorooctanoic acid (PFOA) and perfluorobutanoic acid (PFBA) on oxidative stress and metabolic biomarkers in human neuronal cells (SH-SY5Y). ENVIRONMENT INTERNATIONAL 2024; 190:108864. [PMID: 38986427 DOI: 10.1016/j.envint.2024.108864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 06/04/2024] [Accepted: 06/30/2024] [Indexed: 07/12/2024]
Abstract
Perfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that have attracted considerable attention due to their widespread utilization, resilient characteristics, adverse health implications, and regulatory scrutiny. Despite documented toxicity in living organisms, the precise molecular mechanisms governing the induced adverse effects remain unclear. This study aims to elucidate mechanisms of toxic action by collecting empirical data sets along oxidative stress and metabolic disruption pathways. We investigated the impact of long-chain PFAS (perfluorooctanoic acid (PFOA)) and its short-chain analog (perfluorobutanoic acid (PFBA)) on human neuronal cells (SH-SY5Y). The functionalities of enzymes associated with oxidative stress (catalase and glutathione reductase) and cellular metabolism (lactate dehydrogenase and pyruvate dehydrogenase) were also characterized. Our results reveal that a 24-hour exposure to PFOA and PFBA generated significant levels of reactive oxygen species. Correspondingly, there was a notable decline in catalase and glutathione reductase activities, with PFBA demonstrating a more pronounced effect. High concentrations of PFOA and PFBA reduced metabolic activity. Lactate dehydrogenase activity was only impacted by a high concentration of PFBA, while pyruvate dehydrogenase activity was decreased with PFBA exposure and increased with PFOA exposure. The findings from this study contribute to the knowledge of PFAS and cell interactions and reveal the potential underlying mechanisms of PFAS-induced toxicity.
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Affiliation(s)
- Precious C Obiako
- Department of Environmental Science, Baylor University, Waco, TX, United States
| | - Solomon O Ayisire
- Department of Environmental Science, Baylor University, Waco, TX, United States
| | - Christie M Sayes
- Department of Environmental Science, Baylor University, Waco, TX, United States.
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Yi G, Luo H, Zheng Y, Liu W, Wang D, Zhang Y. Exosomal Proteomics: Unveiling Novel Insights into Lung Cancer. Aging Dis 2024; 16:876-900. [PMID: 38607736 PMCID: PMC11964432 DOI: 10.14336/ad.2024.0409] [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: 03/11/2024] [Accepted: 04/09/2024] [Indexed: 04/14/2024] Open
Abstract
Although significant progress has been made in early lung cancer screening over the past decade, it remains one of the most prevalent and deadliest forms of cancer worldwide. Exosomal proteomics has emerged as a transformative field in lung cancer research, with the potential to redefine diagnostics, prognostic assessments, and therapeutic strategies through the lens of precision medicine. This review discusses recent advances in exosome-related proteomic and glycoproteomic technologies, highlighting their potential to revolutionise lung cancer treatment by addressing issues of heterogeneity, integrating multiomics data, and utilising advanced analytical methods. While these technologies show promise, there are obstacles to overcome before they can be widely implemented, such as the need for standardization, gaps in clinical application, and the importance of dynamic monitoring. Future directions should aim to overcome the challenges to fully utilize the potential of exosomal proteomics in lung cancer. This promises a new era of personalized medicine that leverages the molecular complexity of exosomes for groundbreaking advancements in detection, prognosis, and treatment.
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Affiliation(s)
- Guanhua Yi
- Department of Pulmonary and Critical Care Medicine and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Haixin Luo
- Department of Pulmonary and Critical Care Medicine and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Yalin Zheng
- Department of Pulmonary and Critical Care Medicine and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Wenjing Liu
- Department of Pulmonary and Critical Care Medicine and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Denian Wang
- Department of Pulmonary and Critical Care Medicine and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China.
- Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Yong Zhang
- Department of Pulmonary and Critical Care Medicine and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China.
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Banerjee S, Ansari AA, Upadhyay SP, Mettman DJ, Hibdon JR, Quadir M, Ghosh P, Kambhampati A, Banerjee SK. Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers. Cells 2024; 13:395. [PMID: 38474359 PMCID: PMC10930662 DOI: 10.3390/cells13050395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/12/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.
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Affiliation(s)
- Snigdha Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Affan A. Ansari
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Sunil P. Upadhyay
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Daniel J. Mettman
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Pathology Department, City VA Medical Center, Kansas City, MO 64128, USA
| | - Jamie R. Hibdon
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Mohiuddin Quadir
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58108, USA; (M.Q.); (P.G.)
| | - Pratyusha Ghosh
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58108, USA; (M.Q.); (P.G.)
| | - Anjali Kambhampati
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Sushanta K. Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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He M, Wang L, Yue Z, Feng C, Dai G, Jiang J, Huang H, Ji Q, Zhou M, Li D, Chai W. Development and validation of glycosyltransferase related-gene for the diagnosis and prognosis of head and neck squamous cell carcinoma. Aging (Albany NY) 2024; 16:1750-1766. [PMID: 38244579 PMCID: PMC10866440 DOI: 10.18632/aging.205455] [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: 10/03/2023] [Accepted: 12/14/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous cancer characterized by difficulties in early diagnosis and outcome prediction. Aberrant glycosylated structures produced by the aberrant expression of glycosyltransferases are prevalent in HNSCC. In this study, we aim to construct glycosyltransferase-related gene signatures with diagnostic and prognostic value to better stratify patients with HNSCC and improve their diagnosis and prognosis. METHODS Bioinformatic tools were used to process data of patients with HNSCC from The Cancer Genome Atlas (TCGA) database. The prognostic model was formatted using univariate and multivariate Cox regression methods, while the diagnostic signature was constructed using support vector machine (SVM) and LASSO analysis. The results were verified using the Gene Expression Omnibus (GEO) cohort. The tumor microenvironment and benefits of immune checkpoint inhibitor (ICI) therapy in subgroups defined by glycosyltransferase-related genes were analyzed. Molecular biology experiments, including western blotting, cell counting kit (CCK)-8, colony formation, wound healing, and Transwell assays, were conducted to confirm the oncogenic function of beta-1,4-galactosyltransferase 3 (B4GALT3) in HNSCC. RESULTS We established a five-gene prognostic signature and a 15-gene diagnostic model. Based on the median risk score, patients with low risk had longer overall survival than those in the high-risk group, which was consistent with the results of the GEO cohort. The concrete results suggested that high-risk samples were related to a high tumor protein (TP)53 mutation rate, high infiltration of resting memory cluster of differentiation (CD)4 T cells, resting natural killer (NK) cells, and M0 macrophages, and benefited from ICI therapy. In contrast, the low-risk subgroup was associated with a low TP53 mutation rate; and high infiltration of naive B cells, plasma cells, CD8 T cells, and resting mast cells; and benefited less from ICI therapy. In addition, the diagnostic model had an area under curve (AUC) value of 0.997 and 0.978 in the training dataset and validation cohort, respectively, indicating the high diagnostic potential of the model. Ultimately, the depletion of B4GALT3 significantly hindered the proliferation, migration, and invasion of HNSCC cells. CONCLUSIONS We established two new biomarkers that could provide clinicians with diagnostic, prognostic, and treatment guidance for patients with HNSCC.
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Affiliation(s)
- Miao He
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Li Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Zihan Yue
- Second Clinical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei, China
| | - Chunbo Feng
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Guosheng Dai
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Jinsong Jiang
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Hui Huang
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Qingjun Ji
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Minglang Zhou
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Dapeng Li
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
| | - Wei Chai
- Department of Otorhinolaryngology, Head and Neck Surgery, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
- Scientific Research and Experiment Center, The People’s Hospital of Bozhou, Bozhou 236000, Anhui, China
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10
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Sondag D, de Kleijne FFJ, Castermans S, Chatzakis I, van Geffen M, Van't Veer C, van Heerde WL, Boltje TJ, Rutjes FPJT. Synthesis and Evaluation of Glycosyl Luciferins. Chemistry 2024; 30:e202302547. [PMID: 37849395 DOI: 10.1002/chem.202302547] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/16/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023]
Abstract
Measuring glycosidase activity is important to monitor any aberrations in carbohydrate hydrolase activity, but also for the screening of potential glycosidase inhibitors. To this end, synthetic substrates are needed which provide an enzyme-dependent read-out upon hydrolysis by the glycosidase. Herein, we present two new routes for the synthesis of caged luminescent carbohydrates, which can be used for determining glycosidase activity with a luminescent reporter molecule. The substrates were validated with glycosidase and revealed a clear linear range and enzyme-dependent signal upon the in situ generation of the luciferin moiety from the corresponding nitrile precursors. Besides, we showed that these compounds could directly be synthesized from unprotected glycosyl-α-fluorides in a two-step procedure with yields up to 75 %. The intermediate methyl imidate appeared a key intermediate which also reacted with d-cysteine to give the corresponding d-luciferin substrate rendering this a highly attractive method for synthesizing glycosyl luciferins in good yields.
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Affiliation(s)
- Daan Sondag
- Institute for Molecules and Materials, Radboud University, 6525 AJ, Nijmegen, The Netherlands
| | - Frank F J de Kleijne
- Institute for Molecules and Materials, Radboud University, 6525 AJ, Nijmegen, The Netherlands
| | - Sam Castermans
- Institute for Molecules and Materials, Radboud University, 6525 AJ, Nijmegen, The Netherlands
| | - Isa Chatzakis
- Institute for Molecules and Materials, Radboud University, 6525 AJ, Nijmegen, The Netherlands
| | - Mark van Geffen
- Enzyre BV, Novio Tech Campus, Transistorweg 5-i, 6534 AT, Nijmegen, The Netherlands
| | - Cornelis Van't Veer
- Enzyre BV, Novio Tech Campus, Transistorweg 5-i, 6534 AT, Nijmegen, The Netherlands
| | - Waander L van Heerde
- Enzyre BV, Novio Tech Campus, Transistorweg 5-i, 6534 AT, Nijmegen, The Netherlands
- Department of Haematology, Radboud University Medical Centre, Nijmegen, The Netherlands
- Haemophilia Treatment Centre, Nijmegen Eindhoven Maastricht (HTC-NEM), The Netherlands
| | - Thomas J Boltje
- Institute for Molecules and Materials, Radboud University, 6525 AJ, Nijmegen, The Netherlands
| | - Floris P J T Rutjes
- Institute for Molecules and Materials, Radboud University, 6525 AJ, Nijmegen, The Netherlands
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11
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An SY, Lee JW, Kim HD, Kim KS, Cho JH, Kim CH, Lee YC. Regulatory mechanism for the human glioblastoma cell-specific expression of the human GD1c/GT1a/GQ1b synthase (hST8Sia V) gene. Glycoconj J 2023; 40:621-630. [PMID: 37921922 DOI: 10.1007/s10719-023-10136-5] [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: 07/28/2023] [Revised: 10/05/2023] [Accepted: 10/19/2023] [Indexed: 11/05/2023]
Abstract
In this study we observed that human GD1c/GT1a/GQ1b synthase (hST8Sia V) is particularly expressed in human glioblastoma cells. To address the mechanism regulating human glioblastoma-specific gene expression of the hST8Sia V, after the transcription start site (TSS) was identified by the 5'-rapid amplification of cDNA end with total RNA from human glioblastoma U87MG cells, the 5'-flanking region (2.5 kb) of the hST8Sia V gene was isolated and its promoter activity was examined. By luciferase reporter assay, this 5'-flanking region revealed strong promoter activity in only U-87MG cells, but not in other tissue-derived cancer cells. 5'-deletion mutant analysis showed that the region from -1140 to -494 is crucial for transcription of the hST8Sia V gene in U87MG cells. This region contains the activator protein-1 (AP-1) binding site, the main target of the c-Jun N-terminal kinase (JNK) downstream. The AP-1 binding site at -1043/-1037 was proved to be indispensable for the hST8Sia V gene-specific expression in U87MG cells by site-directed mutagenesis. Moreover, the transcriptional activation of hST8Sia V gene in U87MG cells was strongly inhibited by a specific JNK inhibitor, SP600125. These results suggest that the hST8Sia V gene-specific expression in U87MG cells is controlled by JNK/AP-1 signaling pathway.
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Affiliation(s)
- So-Young An
- Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea
| | - Ji-Won Lee
- Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea
| | - Hee-Do Kim
- Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Kyunggi-Do, 16419, South Korea
| | - Kyoung-Sook Kim
- Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea
| | - Jong-Hyun Cho
- Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea
| | - Cheorl-Ho Kim
- Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Kyunggi-Do, 16419, South Korea.
| | - Young-Choon Lee
- Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea.
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12
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Miller L, Freed-Freundlich M, Shimoni A, Hellou T, Avigdor A, Misgav M, Canaani J. Defining Current Patterns of Blood Product Use during Intensive Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Patients. Transfus Med Hemother 2023; 50:456-468. [PMID: 37899992 PMCID: PMC10601600 DOI: 10.1159/000529595] [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: 09/28/2022] [Accepted: 02/06/2023] [Indexed: 10/31/2023] Open
Abstract
Introduction Blood product transfusion retains a critical role in the supportive care of patients with acute myeloid leukemia (AML). Whereas previous studies have shown increased transfusion dependency to portend inferior outcome, predictive factors of an increased transfusion burden and the prognostic impact of transfusion support have not been assessed recently. Methods/Patients We performed a retrospective analysis on a recent cohort of patients given intensive induction chemotherapy in 2014-2022. Results The analysis comprised 180 patients with a median age of 57 years with 80% designated as de novo AML. Fifty-four patients (31%) were FLT3-ITD mutated, and 73 patients (42%) harbored NPM1. Favorable risk and intermediate risk ELN 2017 patients accounted for 43% and 34% of patients, respectively. The median number of red blood cell (RBC) and platelet units given during induction were 9 and 7 units, respectively. Seventeen patients (9%) received cryoprecipitate, and fresh frozen plasma (FFP) was given to 12 patients (7%). Lower initial hemoglobin and platelet levels were predictive of increased use of RBC (p < 0.0001) and platelet transfusions (p < 0.0001). FFP was significantly associated with induction related mortality (42% vs. 5%; p < 0.0001) and with FLT3-ITD (72% vs. 28%; p = 0.004). Blood group AB experienced improved mean overall survival compared to blood group O patients (4.1 years vs. 2.8 years; p = 0.025). In multivariate analysis, increased number of FFP (hazard ratio [HR], 4.23; 95% confidence interval [CI], 2.1-8.6; p < 0.001) and RBC units (HR, 1.8; 95% CI, 1.2-2.8; p = 0.008) given was associated with inferior survival. Conclusion Transfusion needs during induction crucially impact the clinical trajectory of AML patients.
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Affiliation(s)
- Liron Miller
- Blood Bank and Transfusion Service, Chaim Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
| | - Mor Freed-Freundlich
- Hematology Division, Chaim Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
| | - Avichai Shimoni
- Hematology Division, Chaim Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
| | - Tamer Hellou
- Hematology Division, Chaim Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
| | - Abraham Avigdor
- Hematology Division, Chaim Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
| | - Mudi Misgav
- Blood Bank and Transfusion Service, Chaim Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
| | - Jonathan Canaani
- Hematology Division, Chaim Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
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13
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Xu H, Huang K, Lin Y, Gong H, Ma X, Zhang D. Glycosyltransferase GLT8D1 and GLT8D2 serve as potential prognostic biomarkers correlated with Tumor Immunity in Gastric Cancer. BMC Med Genomics 2023; 16:123. [PMID: 37277853 PMCID: PMC10242987 DOI: 10.1186/s12920-023-01559-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 05/27/2023] [Indexed: 06/07/2023] Open
Abstract
BACKGROUND Glycosylation involved in various biological function, aberrant glycosylation plays an important role in cancer development and progression. Glycosyltransferase 8 domain containing 1 (GLT8D1) and GLT8D2, as members of the glycosyltransferase family proteins, are associated with transferase activity. However, the association between GLT8D1/2 and gastric cancer (GC) remains unclear. We aimed to investigate the potential prognostic value and oncogenic role of GLT8D1/2 in GC. METHODS The relationship between GLT8D1/2 and GC was evaluated through comprehensive bioinformatics approaches. A series of factors like gene expression patterns, Kaplan-Meier survival analyses, Cox regression analyses, prognostic nomogram, calibration curves, ROC curves, function enrichment analyses, tumor immunity association, genetic alterations, and DNA methylation were included. Data and statistical analyses were performed using R software (v3.6.3). RESULTS Both GLT8D1 and GLT8D2 expression were significantly upregulated in GC tissues(n = 414) compared with normal tissues(n = 210), and high expression of GLT8D1/2 was remarkably correlated with poor prognosis for GC patients. Cox regression analyses implied that GLT8D1/2 could act as independent prognostic factors in GC. Furthermore, gene function analyses indicated that multiple signaling pathways involving tumor oncogenesis and development enriched, such as mTOR, cell cycle, MAPK, Notch, Hedgehog, FGF, and PI3K-Akt signaling pathways. Moreover, GLT8D1/2 was significantly associated with immune cell infiltration, immune checkpoint genes, and immune regulators TMB/MSI. CONCLUSION GLT8D1/2 may serve as potential prognostic markers of poor prognosis in GC correlated with tumor immunity. The study provided an insight into identifying potential biomarkers and targets for prognosis, immunotherapy response, and therapy in GC.
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Affiliation(s)
- Huimei Xu
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, P.R. China
- Lanzhou University Second Hospital, Lanzhou, 730030, P.R. China
| | - Ke Huang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730030, P.R. China
| | - Yimin Lin
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, P.R. China
- Lanzhou University Second Hospital, Lanzhou, 730030, P.R. China
| | - Hang Gong
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, P.R. China
- Lanzhou University Second Hospital, Lanzhou, 730030, P.R. China
| | - Xueni Ma
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou, 730030, P.R. China
- Lanzhou University Second Hospital, Lanzhou, 730030, P.R. China
| | - Dekui Zhang
- Lanzhou University Second Hospital, Lanzhou, 730030, P.R. China.
- Key Laboratory of Digestive Diseases of Lanzhou University Second Hospital, Lanzhou, 730030, P.R. China.
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14
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Lam KWK, Chau JHC, Yu EY, Sun F, Lam JWY, Ding D, Kwok RTK, Sun J, He X, Tang BZ. An Alkaline Phosphatase-Responsive Aggregation-Induced Emission Photosensitizer for Selective Imaging and Photodynamic Therapy of Cancer Cells. ACS NANO 2023; 17:7145-7156. [PMID: 37067178 DOI: 10.1021/acsnano.2c08855] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Fluorescence-guided photodynamic therapy (PDT) has been considered as an emerging strategy for precise cancer treatment by making use of photosensitizers (PSs) with reactive oxygen species (ROS) generation. Some efficient PSs have been reported in recent years, but multifunctional PSs that are responsive to cancer-specific biomarkers are rarely reported. In this study, we introduced a phosphate group as a cancer-specific biomarker of alkaline phosphatase (ALP) on a PS with the features of aggregation-induced emission (AIE) for cancer cell imaging and therapy. In cancer cells with high ALP expression, the phosphate group on the AIE probe is selectively hydrolyzed by ALP. Consequently, the hydrophobic probe residue is aggregated in aqueous media and gives a "turn on" fluorescent response. Moreover, fluorescence-guided PDT was realized by the aggregates of probe residue with strong ROS generation efficiency under white light irradiation. Overall, this work presents a strategy of applying ALP-responsive AIE PS for specific imaging cancer cells and succeeding with specific PDT upon the cancer biomarker stimulated responsive reactions.
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Affiliation(s)
- Kristy W K Lam
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
| | - Joe H C Chau
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
| | - Eric Y Yu
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
| | - Feiyi Sun
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
| | - Jacky W Y Lam
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
- HKUST-Shenzhen Research Institute, No. 9 Yuexing first RD, South Area Hi-Tech Park, Nanshan, Shenzhen 518057, China
| | - Dan Ding
- Key Laboratory of Bioactive Materials Ministry of Education and College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Ryan T K Kwok
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
- HKUST-Shenzhen Research Institute, No. 9 Yuexing first RD, South Area Hi-Tech Park, Nanshan, Shenzhen 518057, China
| | - Jianwei Sun
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
| | - Xuewen He
- The Key Lab of Health Chemistry and Molecular Diagnosis of Suzhou, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Ben Zhong Tang
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China
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15
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Alvarez MR, Zhou Q, Tena J, Barboza M, Wong M, Xie Y, Lebrilla CB, Cabanatan M, Barzaga MT, Tan-Liu N, Heralde FM, Serrano L, Nacario RC, Completo GC. Glycomic, Glycoproteomic, and Proteomic Profiling of Philippine Lung Cancer and Peritumoral Tissues: Case Series Study of Patients Stages I-III. Cancers (Basel) 2023; 15:cancers15051559. [PMID: 36900350 PMCID: PMC10001221 DOI: 10.3390/cancers15051559] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Lung cancer is the leading cause of cancer death and non-small cell lung carcinoma (NSCLC) accounting for majority of lung cancers. Thus, it is important to find potential biomarkers, such as glycans and glycoproteins, which can be used as diagnostic tools against NSCLC. Here, the N-glycome, proteome, and N-glycosylation distribution maps of tumor and peritumoral tissues of Filipino lung cancer patients (n = 5) were characterized. We present several case studies with varying stages of cancer development (I-III), mutation status (EGFR, ALK), and biomarker expression based on a three-gene panel (CD133, KRT19, and MUC1). Although the profiles of each patient were unique, specific trends arose that correlated with the role of aberrant glycosylation in cancer progression. Specifically, we observed a general increase in the relative abundance of high-mannose and sialofucosylated N-glycans in tumor samples. Analysis of the glycan distribution per glycosite revealed that these sialofucosylated N-glycans were specifically attached to glycoproteins involved in key cellular processes, including metabolism, cell adhesion, and regulatory pathways. Protein expression profiles showed significant enrichment of dysregulated proteins involved in metabolism, adhesion, cell-ECM interactions, and N-linked glycosylation, supporting the protein glycosylation results. The present case series study provides the first demonstration of a multi-platform mass-spectrometric analysis specifically for Filipino lung cancer patients.
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Affiliation(s)
- Michael Russelle Alvarez
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
- Institute of Chemistry, University of the Philippines Los Baños, Laguna 4031, Philippines
| | - Qingwen Zhou
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
| | - Jennyfer Tena
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
| | - Mariana Barboza
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
| | - Maurice Wong
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
| | - Yixuan Xie
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
| | - Carlito B. Lebrilla
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA
| | - Michelle Cabanatan
- Molecular Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1100, Philippines
| | - Ma. Teresa Barzaga
- Molecular Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1100, Philippines
- College of Medicine, De La Salle Health Sciences Institute, Cavite 4114, Philippines
| | - Nelia Tan-Liu
- Molecular Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1100, Philippines
| | - Francisco M. Heralde
- Molecular Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1100, Philippines
- College of Medicine, University of the Philippines Manila, Manila City 1000, Philippines
| | - Luster Serrano
- Institute of Chemistry, University of the Philippines Los Baños, Laguna 4031, Philippines
| | - Ruel C. Nacario
- Institute of Chemistry, University of the Philippines Los Baños, Laguna 4031, Philippines
| | - Gladys Cherisse Completo
- Institute of Chemistry, University of the Philippines Los Baños, Laguna 4031, Philippines
- Correspondence:
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16
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Alvarez MRS, Grijaldo SJB, Nacario RC, Rabajante JF, Heralde FM, Lebrilla CB, Completo GC. In silico screening-based discovery of inhibitors against glycosylation proteins dysregulated in cancer. J Biomol Struct Dyn 2023; 41:1540-1552. [PMID: 34989310 DOI: 10.1080/07391102.2021.2022534] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Targeting enzymes associated with the biosynthesis of aberrant glycans is an under-utilized strategy in discovering potential inhibitors or drugs against cancer. The formation of cancer-associated glycans is mainly due to the dysregulated expression of glycosyltransferases and glycosidases, which play crucial roles in maintaining cellular structure and function. We screened a database of more than 14,000 compounds consisting of natural products and drugs for inhibition against four glycosylation enzymes - Alpha1-6FucT, ST6Gal1, ERMan1, and GlcNAcT-V. The top inhibitors identified against each enzyme were subsequently analyzed for potential binding against all four enzymes. In silico screening results show several promising candidates that could potentially inhibit all four enzymes: (1) Amb20622156 (demethylwedelolactone) [ERMan1: -9.3 kcal/mol; Alpha1-6FucT: -7.3 kcal/mol; ST6Gal1: -8.4 kcal/mol; GlcNAcT-V: -7.2 kcal/mol], (2) Amb22173588 (1,2-dihydrotanshinone I) [ERMan1: -9.3 kcal/mol; Alpha1-6FucT: -6.1 kcal/mol; ST6Gal1: -9.2 kcal/mol; GlcNAcT-V: -7.9 kcal/mol], and (3) Amb22173591 (tanshinol B) [ERMan1: -9.3 kcal/mol; Alpha1-6FucT: -6.0 kcal/mol; ST6Gal1: -9.8 kcal/mol; GlcNAcT-V: -7.7 kcal/mol]. Drug-enzyme active site residue interaction analyses show that the putative inhibitors form non-covalent bonding interactions with key active site residues in each enzyme, suggesting critical target residues in the four enzymes' active sites. Furthermore, pharmacokinetic property prediction analysis using pkCSM indicates that all of these inhibitors have good ADMETox properties (i.e., log P < 5, Caco-2 permeability > 0.90, intestinal absorption > 30%, skin permeability>-2.5, CNS permeability <-3, maximum tolerated dose < 0.477, minnow toxicity<-0.3). The in silico docking approach to glycosylation enzyme inhibitor prediction could help guide and streamline the discovery of novel inhibitors against enzymes involved in aberrant protein glycosylation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Michael Russelle S Alvarez
- Institute of Chemistry, University of the Philippines Los Baños, Los Baños, Laguna, Philippines.,College of Arts and Sciences, Isabela State University, Echague, Isabela, Philippines
| | - Sheryl Joyce B Grijaldo
- Institute of Chemistry, University of the Philippines Los Baños, Los Baños, Laguna, Philippines
| | - Ruel C Nacario
- Institute of Chemistry, University of the Philippines Los Baños, Los Baños, Laguna, Philippines
| | - Jomar F Rabajante
- Institute of Mathematical Sciences and Physics, University of the Philippines Los Baños, Los Baños, Laguna, Philippines
| | - Francisco M Heralde
- Molecular Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City, Philippines
| | - Carlito B Lebrilla
- Department of Chemistry, University of California Davis, Davis, California, USA
| | - Gladys C Completo
- Institute of Chemistry, University of the Philippines Los Baños, Los Baños, Laguna, Philippines
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17
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Visconti A, Rossi N, Deriš H, Lee KA, Hanić M, Trbojević-Akmačić I, Thomas AM, Bolte LA, Björk JR, Hooiveld-Noeken JS, Board R, Harland M, Newton-Bishop J, Harries M, Sacco JJ, Lorigan P, Shaw HM, de Vries EGE, Fehrmann RSN, Weersma RK, Spector TD, Nathan P, Hospers GAP, Sasieni P, Bataille V, Lauc G, Falchi M. Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma. BMC Cancer 2023; 23:166. [PMID: 36805683 PMCID: PMC9938582 DOI: 10.1186/s12885-023-10511-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 01/04/2023] [Indexed: 02/20/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response. METHODS We aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment. RESULTS We observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone. CONCLUSION While changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response.
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Affiliation(s)
- Alessia Visconti
- Department of Twins Research & Genetics Epidemiology, King's College London, London, UK
| | - Niccolò Rossi
- Department of Twins Research & Genetics Epidemiology, King's College London, London, UK
| | - Helena Deriš
- Genos Glycoscience Research Laboratory, Zagreb, Croatia
| | - Karla A Lee
- Department of Twins Research & Genetics Epidemiology, King's College London, London, UK
| | - Maja Hanić
- Genos Glycoscience Research Laboratory, Zagreb, Croatia
| | | | | | - Laura A Bolte
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Johannes R Björk
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center, Groningen, The Netherlands
| | | | - Ruth Board
- Department of Oncology, Lancashire Teaching Hospitals NHS Trust, Chorley, UK
| | - Mark Harland
- Division of Haematology and Immunology, Institute of Medical Research at St. James', University of Leeds, Leeds, UK
| | - Julia Newton-Bishop
- Division of Haematology and Immunology, Institute of Medical Research at St. James', University of Leeds, Leeds, UK
| | - Mark Harries
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Joseph J Sacco
- Liverpool Clatterbridge Cancer Centre, Liverpool, UK
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Paul Lorigan
- The Christie NHS Foundation Trust, Manchester, UK
| | - Heather M Shaw
- Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK
| | - Elisabeth G E de Vries
- Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudolf S N Fehrmann
- Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Tim D Spector
- Department of Twins Research & Genetics Epidemiology, King's College London, London, UK
| | - Paul Nathan
- Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK
| | - Geke A P Hospers
- Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter Sasieni
- School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Veronique Bataille
- Department of Twins Research & Genetics Epidemiology, King's College London, London, UK.
- Department of Dermatology, Mount Vernon Cancer Centre, Northwood, UK.
- Department of Dermatology, West Herts NHS Trust, Herts, UK.
| | - Gordan Lauc
- Genos Glycoscience Research Laboratory, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Mario Falchi
- Department of Twins Research & Genetics Epidemiology, King's College London, London, UK.
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18
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Li H, Yang F, Chang K, Yu X, Guan F, Li X. The synergistic function of long and short forms of β4GalT1 in p53-mediated drug resistance in bladder cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119409. [PMID: 36513218 DOI: 10.1016/j.bbamcr.2022.119409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 11/25/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022]
Abstract
β1,4-galactosyltransferase-1 (β4GalT1) is a type II membrane protein that catalyzes the transfer of galactose (Gal) from UDP-Gal to N-acetylglucosamine (GlcNAc) and forms a LacNAc structure. β4GalT1 has a long form (termed β4GalT1-L) and a short form (termed β4GalT1-S) in mammalian cells. Although β4GalT1 has been proven to play an important role in many biological and pathological processes, such as differentiation, immune responses and cancer development, the different functions of the two β4GalT1 forms remain ambiguous. In this study, we demonstrated that total β4GalT1 was upregulated in bladder cancer. Overexpression of β4GalT1-S, but not β4GalT1-L, increased drug resistance in bladder epithelial cells by upregulating p53 expression. Glycoproteomic analysis revealed that the substrate specificities of the two β4GalT1 forms were different. Among the LacNAcylated proteins, the E3 ligase MDM2 could be preferentially modified by β4GalT1-L compared to β4GalT1-S, and this modification could increase the binding of MDM2 and p53 and further facilitate the degradation of p53. Our data proved that the two forms of β4GalT1 could synergistically regulate p53-mediated cell survival under chemotherapy treatment. These results provide insights into the role of β4GalT1-L and β4GalT1-S and suggest their differentially important implications in the development of bladder cancer.
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Affiliation(s)
- Hongjiao Li
- Key Laboratory of Resource Biology and Biotechnology Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Fenfang Yang
- Key Laboratory of Resource Biology and Biotechnology Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Kaijing Chang
- Key Laboratory of Resource Biology and Biotechnology Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Xinwen Yu
- Key Laboratory of Resource Biology and Biotechnology Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology Western China, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China.
| | - Xiang Li
- Institute of Hematology, School of Medicine, Northwest University, Xi'an, China.
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19
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Li Y, Lih TSM, Dhanasekaran SM, Mannan R, Chen L, Cieslik M, Wu Y, Lu RJH, Clark DJ, Kołodziejczak I, Hong R, Chen S, Zhao Y, Chugh S, Caravan W, Naser Al Deen N, Hosseini N, Newton CJ, Krug K, Xu Y, Cho KC, Hu Y, Zhang Y, Kumar-Sinha C, Ma W, Calinawan A, Wyczalkowski MA, Wendl MC, Wang Y, Guo S, Zhang C, Le A, Dagar A, Hopkins A, Cho H, Leprevost FDV, Jing X, Teo GC, Liu W, Reimers MA, Pachynski R, Lazar AJ, Chinnaiyan AM, Van Tine BA, Zhang B, Rodland KD, Getz G, Mani DR, Wang P, Chen F, Hostetter G, Thiagarajan M, Linehan WM, Fenyö D, Jewell SD, Omenn GS, Mehra R, Wiznerowicz M, Robles AI, Mesri M, Hiltke T, An E, Rodriguez H, Chan DW, Ricketts CJ, Nesvizhskii AI, Zhang H, Ding L. Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness. Cancer Cell 2023; 41:139-163.e17. [PMID: 36563681 PMCID: PMC9839644 DOI: 10.1016/j.ccell.2022.12.001] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 08/18/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022]
Abstract
Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.
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Affiliation(s)
- Yize Li
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Tung-Shing M Lih
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA
| | - Saravana M Dhanasekaran
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Rahul Mannan
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lijun Chen
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA
| | - Marcin Cieslik
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yige Wu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Rita Jiu-Hsien Lu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - David J Clark
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA
| | - Iga Kołodziejczak
- International Institute for Molecular Oncology, 60-203 Poznań, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Runyu Hong
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Siqi Chen
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Yanyan Zhao
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Seema Chugh
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wagma Caravan
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Nataly Naser Al Deen
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Noshad Hosseini
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Karsten Krug
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Yuanwei Xu
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
| | - Kyung-Cho Cho
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA
| | - Yingwei Hu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA
| | - Yuping Zhang
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Chandan Kumar-Sinha
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Weiping Ma
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Anna Calinawan
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Matthew A Wyczalkowski
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Michael C Wendl
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Yuefan Wang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA
| | - Shenghao Guo
- Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
| | - Cissy Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA
| | - Anne Le
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Aniket Dagar
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Alex Hopkins
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hanbyul Cho
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Xiaojun Jing
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Guo Ci Teo
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wenke Liu
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Melissa A Reimers
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA; Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Russell Pachynski
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA; Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Alexander J Lazar
- Departments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Arul M Chinnaiyan
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Brian A Van Tine
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Bing Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Karin D Rodland
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - Gad Getz
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - D R Mani
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Pei Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Feng Chen
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO 63130, USA
| | | | | | - W Marston Linehan
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - David Fenyö
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Scott D Jewell
- Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Gilbert S Omenn
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rohit Mehra
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Maciej Wiznerowicz
- International Institute for Molecular Oncology, 60-203 Poznań, Poland; Heliodor Swiecicki Clinical Hospital in Poznań, ul. Przybyszewskiego 49, 60-355 Poznań, Poland; Poznań University of Medical Sciences, 61-701 Poznań, Poland
| | - Ana I Robles
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA
| | - Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA
| | - Tara Hiltke
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA
| | - Eunkyung An
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA
| | - Daniel W Chan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christopher J Ricketts
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Alexey I Nesvizhskii
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Li Ding
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63130, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA.
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20
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Peric L, Vukadin S, Petrovic A, Kuna L, Puseljic N, Sikora R, Rozac K, Vcev A, Smolic M. Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer. Biomedicines 2022; 10:3265. [PMID: 36552021 PMCID: PMC9775348 DOI: 10.3390/biomedicines10123265] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/25/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
Although we are lately witnessing major improvements in breast cancer treatment and patient outcomes, there is still a significant proportion of patients not receiving efficient therapy. More precisely, patients with triple-negative breast cancer or any type of metastatic disease. Currently available prognostic and therapeutic biomarkers are not always applicable and oftentimes lack precision. The science of glycans is a relatively new scientific approach to better characterize malignant transformation and tumor progression. In this review, we summarize the most important information about glycosylation characteristics in breast cancer cells and how different glycoproteins and enzymes involved in glycosylation could serve as more precise biomarkers, as well as new therapeutic targets.
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Affiliation(s)
- Luka Peric
- Department of Oncology, University Hospital Osijek, 31000 Osijek, Croatia
| | - Sonja Vukadin
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Ana Petrovic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Lucija Kuna
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Nora Puseljic
- Pediatric Clinic, University Hospital Osijek, 31000 Osijek, Croatia
| | - Renata Sikora
- Department of Dental Medicine, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Health Center Osijek-Baranja County, 31000 Osijek, Croatia
| | - Karla Rozac
- Department of Anatomy, Histology, Embryology, Pathological Anatomy and Pathological Histology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Aleksandar Vcev
- Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
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21
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Alvarez MS, Zhou Q, Tena J, Lebrilla CB, Completo GC, Heralde FM, Cabanatan M, Barzaga MT, Tan-Liu N, Ladrera GI, Danguilan JL, Rabajante J, Padolina I, Nacario RC. N-Glycan and Glycopeptide Serum Biomarkers in Philippine Lung Cancer Patients Identified Using Liquid Chromatography-Tandem Mass Spectrometry. ACS OMEGA 2022; 7:40230-40240. [PMID: 36385894 PMCID: PMC9647785 DOI: 10.1021/acsomega.2c05111] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/09/2022] [Indexed: 06/16/2023]
Abstract
Aberrant glycosylation has been extensively reported in cancer, with fundamental changes in the glycosylation patterns of cell-surface and secreted proteins largely occurring during cancer progression. As such, serum glycan and glycopeptide biomarkers have been discovered using mass spectrometry and proposed for cancer detection. Here, we report for the first time potential serum N-glycan and glycopeptide biomarkers for Philippine lung cancer patients. The N-glycan and glycoprotein profiles of a cohort (n = 26 patients, n = 22 age- and gender-matched) of lung cancer patients were analyzed and compared to identify potential N-glycan and glycopeptide serum biomarkers using nano-QToF-MS/MS and ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry dynamic multiple monitoring methods, respectively. Statistical analyses identified differential N-glycan and glycopeptide abundances. The N-glycans were mostly sialylated and sialofucosylated branched structures. The glycopeptides involved proteins in complement and coagulation cascades (p adj = 6.418 × 10-4), innate immunity (p adj = 6.094 × 10-3), acute inflammatory response (p adj = 6.404 × 10-5), defense response (p adj = 2.082 × 10-4), complement activation pathways (p adj = 1.895 × 10-2), and immunoglobulin-mediated immune response pathways (p adj = 4.818 × 10-2). Biomarker models were constructed using serum N-glycans [area under the curve (AUC) = 0.775; 95% CI: 0.617-0.931] and glycopeptides (AUC = 0.959; 95% CI: 0.85-1.0), with glycopeptides having higher accuracies than N-glycans. The results suggest that in the Philippine lung cancer patient sera, specific N-glycans and site-specific glycans are differentially expressed between cases and controls. This report represents the first serum glycan and glycopeptide biomarkers of Philippine lung cancer patients, further demonstrating the utility of mass spectrometry-based glycomic and glycoproteomic methods.
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Affiliation(s)
- Michael
Russelle S. Alvarez
- Institute
of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, Laguna 4031, Philippines
- Department
of Chemistry, University of California Davis, Davis, California 95616-5270, United States
| | - Qingwen Zhou
- Department
of Chemistry, University of California Davis, Davis, California 95616-5270, United States
| | - Jennyfer Tena
- Department
of Chemistry, University of California Davis, Davis, California 95616-5270, United States
| | - Carlito B. Lebrilla
- Department
of Chemistry, University of California Davis, Davis, California 95616-5270, United States
| | - Gladys C. Completo
- Institute
of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, Laguna 4031, Philippines
| | - Francisco M. Heralde
- Molecular
Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1104, Philippines
- Department
of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines−Manila, Manila, NCR 1159, Philippines
| | - Michelle Cabanatan
- Molecular
Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1104, Philippines
| | - Ma. Teresa Barzaga
- Molecular
Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1104, Philippines
- College
of Medicine, De La Salle Health Sciences
Institute, Cavite 4114, Philippines
| | - Nelia Tan-Liu
- Molecular
Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1104, Philippines
| | - Guia Imelda Ladrera
- Molecular
Diagnostics and Cellular Therapeutics Laboratory, Lung Center of the Philippines, Quezon City 1104, Philippines
| | - Jose Luis Danguilan
- Department
of Thoracic Surgery and Anesthesia, Lung
Center of the Philippines, Quezon
City 1104, Philippines
| | - Jomar Rabajante
- Institute
of Mathematical Sciences and Physics, College of Arts and Sciences, University of the Philippines Los Baños, Laguna 4031, Philippines
| | - Isagani Padolina
- Pascual
Pharma Corp, Core Research and Development Laboratory, UPLB Science and Technology Park, Los Baños, Laguna 4031, Philippines
| | - Ruel C. Nacario
- Institute
of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, Laguna 4031, Philippines
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22
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Alvarez MRS, Zhou Q, Grijaldo SJB, Lebrilla CB, Nacario RC, Heralde FM, Rabajante JF, Completo GC. An Integrated Mass Spectrometry-Based Glycomics-Driven Glycoproteomics Analytical Platform to Functionally Characterize Glycosylation Inhibitors. Molecules 2022; 27:3834. [PMID: 35744954 PMCID: PMC9228227 DOI: 10.3390/molecules27123834] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer progression is linked to aberrant protein glycosylation due to the overexpression of several glycosylation enzymes. These enzymes are underexploited as potential anticancer drug targets and the development of rapid-screening methods and identification of glycosylation inhibitors are highly sought. An integrated bioinformatics and mass spectrometry-based glycomics-driven glycoproteomics analysis pipeline was performed to identify an N-glycan inhibitor against lung cancer cells. Combined network pharmacology and in silico screening approaches were used to identify a potential inhibitor, pictilisib, against several glycosylation-related proteins, such as Alpha1-6FucT, GlcNAcT-V, and Alpha2,6-ST-I. A glycomics assay of lung cancer cells treated with pictilisib showed a significant reduction in the fucosylation and sialylation of N-glycans, with an increase in high mannose-type glycans. Proteomics analysis and in vitro assays also showed significant upregulation of the proteins involved in apoptosis and cell adhesion, and the downregulation of proteins involved in cell cycle regulation, mRNA processing, and protein translation. Site-specific glycoproteomics analysis further showed that glycoproteins with reduced fucosylation and sialylation were involved in apoptosis, cell adhesion, DNA damage repair, and chemical response processes. To determine how the alterations in N-glycosylation impact glycoprotein dynamics, modeling of changes in glycan interactions of the ITGA5-ITGB1 (Integrin alpha 5-Integrin beta-1) complex revealed specific glycosites at the interface of these proteins that, when highly fucosylated and sialylated, such as in untreated A549 cells, form greater hydrogen bonding interactions compared to the high mannose-types in pictilisib-treated A549 cells. This study highlights the use of mass spectrometry to identify a potential glycosylation inhibitor and assessment of its impact on cell surface glycoprotein abundance and protein-protein interaction.
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Affiliation(s)
- Michael Russelle S. Alvarez
- Institute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, Los Baños 4031, Philippines; (M.R.S.A.); (S.J.B.G.); (R.C.N.)
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA; (Q.Z.); (C.B.L.)
| | - Qingwen Zhou
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA; (Q.Z.); (C.B.L.)
| | - Sheryl Joyce B. Grijaldo
- Institute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, Los Baños 4031, Philippines; (M.R.S.A.); (S.J.B.G.); (R.C.N.)
| | - Carlito B. Lebrilla
- Department of Chemistry, University of California Davis, Davis, CA 95616, USA; (Q.Z.); (C.B.L.)
| | - Ruel C. Nacario
- Institute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, Los Baños 4031, Philippines; (M.R.S.A.); (S.J.B.G.); (R.C.N.)
| | | | - Jomar F. Rabajante
- Institute of Mathematical Sciences and Physics, College of Arts and Sciences, University of the Philippines Los Baños, Los Baños 4031, Philippines;
| | - Gladys C. Completo
- Institute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, Los Baños 4031, Philippines; (M.R.S.A.); (S.J.B.G.); (R.C.N.)
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23
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Phang R, Lin CH. Synthesis of Type-I and Type-II LacNAc-Repeating Oligosaccharides as the Backbones of Tumor-Associated Lewis Antigens. Front Immunol 2022; 13:858894. [PMID: 35281035 PMCID: PMC8905443 DOI: 10.3389/fimmu.2022.858894] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/04/2022] [Indexed: 11/29/2022] Open
Abstract
Type-I and Type-II LacNAc are Gal-GlcNAc disaccharides bearing a β1,3- or β1,4-linkage respectively. They exist as the backbones of Lewis antigens that are highly expressed in several cancers. Owing to the promise of developing carbohydrate-based anti-cancer vaccines, glycan synthesis at a large scale is indeed an important task. Synthesis of Type-I and Type-II tandem repeat oligomers has been hampered by the presence of GlcNAc residues. Particularly, N-protecting group plays a determining role in affecting glycosyl donor’s reactivity and acceptor’s nucleophilicity. This review discusses several representative studies that assembled desirable glycans in an efficient manner, such as chemoselective one-pot synthesis and chemoenzymatic methods. Additionally, we also highlight solutions that have been offered to tackle long-lasting problems, e.g., prevention of the oxazoline formation and change of donor/acceptor reactivity. In retrospect of scientific achievements, we present the current restrictions and remaining challenges in this less explored frontier.
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Affiliation(s)
- Riping Phang
- Department of Chemistry, National Taiwan University, Taipei, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Chun-Hung Lin
- Department of Chemistry, National Taiwan University, Taipei, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
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24
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Saad AA. Targeting cancer-associated glycans as a therapeutic strategy in leukemia. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2049901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Ashraf Abdullah Saad
- Unit of Pediatric Hematologic Oncology and BMT, Sultan Qaboos University Hospital, Muscat, Oman
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25
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Esmail S, Manolson MF. Advances in understanding N-glycosylation structure, function, and regulation in health and disease. Eur J Cell Biol 2021; 100:151186. [PMID: 34839178 DOI: 10.1016/j.ejcb.2021.151186] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/14/2021] [Accepted: 11/18/2021] [Indexed: 01/17/2023] Open
Abstract
N-linked glycosylation is a post-translational modification crucial for membrane protein folding, stability and other cellular functions. Alteration of membrane protein N-glycans is implicated in wide range of pathological conditions including cancer metastasis, chronic inflammatory diseases, and viral pathogenesis. Even though the roles of N-glycans have been studied extensively, our knowledge of their mechanisms remains unclear due to the lack of detailed structural analysis of the N-glycome. Mapping the N-glycome landscape will open new avenues to explore disease mechanisms and identify novel therapeutic targets. This review discusses the diverse structure of N-linked glycans, the function and regulation of N-glycosylation in health and disease, and ends with a focus on recent approaches to target N-glycans in rheumatoid arthritis and cancer metastasis.
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Affiliation(s)
- Sally Esmail
- Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
| | - Morris F Manolson
- Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada
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26
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Calatrava-Pérez E, Marchetti LA, McManus GJ, Lynch DM, Elmes RBP, Williams DC, Gunnlaugsson T, Scanlan EM. Real-Time Multi-Photon Tracking and Bioimaging of Glycosylated Theranostic Prodrugs upon Specific Enzyme Triggered Release. Chemistry 2021; 28:e202103858. [PMID: 34820925 DOI: 10.1002/chem.202103858] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Indexed: 01/22/2023]
Abstract
Real-time tracking of prodrug uptake, delivery and activation in vivo represents a major challenge for prodrug development. Herein, we demonstrate the use of novel glycosylated theranostics of the cancer pharmacophore Amonafide in highly-selective, enzymatic triggered release. We show that the use of endogenous enzymes for activated release of the therapeutic component can be observed, in real time, and monitored using one and two-photon bioimaging, offering unique insight into the prodrug pharmacokinetic profile. Furthermore, we demonstrate that the potent cytotoxicity of Amonafide is preserved using this targeted approach.
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Affiliation(s)
- Elena Calatrava-Pérez
- School of Chemistry Trinity Biomedical Sciences Institute (TBSI) Trinity College Dublin, The University of Dublin, D02 R590, Dublin 2, Ireland
| | - Luke A Marchetti
- Chemistry Department, Science Building Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland.,Maynooth University Human Health Research Institute Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland
| | - Gavin J McManus
- School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute (TBSI) Trinity College Dublin, The University of Dublin, D02 R590, Dublin 2, Ireland
| | - Dylan M Lynch
- School of Chemistry Trinity Biomedical Sciences Institute (TBSI) Trinity College Dublin, The University of Dublin, D02 R590, Dublin 2, Ireland
| | - Robert B P Elmes
- Chemistry Department, Science Building Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland.,Maynooth University Human Health Research Institute Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland
| | - D Clive Williams
- School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute (TBSI) Trinity College Dublin, The University of Dublin, D02 R590, Dublin 2, Ireland
| | - Thorfinnur Gunnlaugsson
- School of Chemistry Trinity Biomedical Sciences Institute (TBSI) Trinity College Dublin, The University of Dublin, D02 R590, Dublin 2, Ireland
| | - Eoin M Scanlan
- School of Chemistry Trinity Biomedical Sciences Institute (TBSI) Trinity College Dublin, The University of Dublin, D02 R590, Dublin 2, Ireland
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27
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Guzman NA, Guzman DE. Immunoaffinity Capillary Electrophoresis in the Era of Proteoforms, Liquid Biopsy and Preventive Medicine: A Potential Impact in the Diagnosis and Monitoring of Disease Progression. Biomolecules 2021; 11:1443. [PMID: 34680076 PMCID: PMC8533156 DOI: 10.3390/biom11101443] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/22/2021] [Accepted: 09/29/2021] [Indexed: 01/08/2023] Open
Abstract
Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in identification and characterization of a distinct functional pool of proteins known as proteoforms. Proteoforms are defined as all of the different molecular forms of a protein derived from a single gene caused by genetic variations, alternative spliced RNA transcripts and post-translational modifications. Monitoring the structural changes of each proteoform of a particular protein is essential to elucidate the complex molecular mechanisms that guide the course of disease. Clinical proteomics therefore holds the potential to offer further insight into disease pathology, progression, and prevention. Nevertheless, more technologically advanced diagnostic methods are needed to improve the reliability and clinical applicability of proteomics in preventive medicine. In this manuscript, we review the use of immunoaffinity capillary electrophoresis (IACE) as an emerging powerful diagnostic tool to isolate, separate, detect and characterize proteoform biomarkers obtained from liquid biopsy. IACE is an affinity capture-separation technology capable of isolating, concentrating and analyzing a wide range of biomarkers present in biological fluids. Isolation and concentration of target analytes is accomplished through binding to one or more biorecognition affinity ligands immobilized to a solid support, while separation and analysis are achieved by high-resolution capillary electrophoresis (CE) coupled to one or more detectors. IACE has the potential to generate rapid results with significant accuracy, leading to reliability and reproducibility in diagnosing and monitoring disease. Additionally, IACE has the capability of monitoring the efficacy of therapeutic agents by quantifying companion and complementary protein biomarkers. With advancements in telemedicine and artificial intelligence, the implementation of proteoform biomarker detection and analysis may significantly improve our capacity to identify medical conditions early and intervene in ways that improve health outcomes for individuals and populations.
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Affiliation(s)
| | - Daniel E. Guzman
- Princeton Biochemicals, Inc., Princeton, NJ 08543, USA;
- Division of Hospital Medicine, Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA
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28
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Tikhonov A, Smoldovskaya O, Feyzkhanova G, Kushlinskii N, Rubina A. Glycan-specific antibodies as potential cancer biomarkers: a focus on microarray applications. Clin Chem Lab Med 2021; 58:1611-1622. [PMID: 32324152 DOI: 10.1515/cclm-2019-1161] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Glycosylation is one of the most common posttranslational modifications of proteins and lipids. In the case of tumors, cell transformation accompanied by aberrant glycosylation results in the expression of tumor-associated glycans that promote tumor invasion. As part of the innate immunity, anti-glycan antibodies recognize tumor-associated glycans, and these antibodies can be present in the bloodstream in the early stages of cancer. Recently, anti-glycan antibody profiles have been of interest in various cancer studies. Novel advantages in the field of analytical techniques have simplified the analysis of anti-glycan antibodies and made it easier to have more comprehensive knowledge about their functions. One of the robust approaches for studying anti-glycan antibodies engages in microarray technology. The analysis of glycan microarrays can provide more expanded information to simultaneously specify or suggest the role of antibodies to a wide variety of glycans in the progression of different diseases, therefore making it possible to identify new biomarkers for diagnosing cancer and/or the state of the disease. Thus, in this review, we discuss antibodies to various glycans, their application for diagnosing cancer and one of the most promising tools for the investigation of these molecules, microarrays.
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Affiliation(s)
- Aleksei Tikhonov
- Laboratory of Biological Microchips, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Olga Smoldovskaya
- Laboratory of Biological Microchips, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Guzel Feyzkhanova
- Laboratory of Biological Microchips, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Nikolay Kushlinskii
- Laboratory of Clinical Biochemistry, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» оf the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Alla Rubina
- Laboratory of Biological Microchips, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
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29
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Saini A, Singh J, Kumar S. Optically superior fluorescent probes for selective imaging of cells, tumors, and reactive chemical species. Org Biomol Chem 2021; 19:5208-5236. [PMID: 34037048 DOI: 10.1039/d1ob00509j] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Fluorescent chemical probes have become powerful tools to study biological events in living cells. They provide a great opportunity to quantitatively and qualitatively analyze the physiological and biochemical properties of living cells in real time. The ability of researchers to manipulate these probes for a desired specific purpose has turned many heads in the scientific community. Despite a slow start, fluorescent probe research has seen exponential growth over the last decade in the world. This change required some adventurous and creative scientists from different fields-like biology, medicine, and chemistry-to come together to facilitate the constant expansion of this field. This review article introduces some fundamental concepts related to fluorescent probe designing and development. It also summarizes various fluorescent probes with superior optical properties used in fields like cell biology, cellular imaging, medical research, and cancer diagnosis. It is hoped that this article will encourage more young and creative scientists to contribute their talents to this field.
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Affiliation(s)
- Abhishek Saini
- Department of Chemistry, Hansraj College, University of Delhi, Delhi-110007, India.
| | - Jyoti Singh
- Department of Chemistry, Hansraj College, University of Delhi, Delhi-110007, India.
| | - Sonu Kumar
- Department of Chemistry, Hansraj College, University of Delhi, Delhi-110007, India.
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30
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Sun X, He Z, Guo L, Wang C, Lin C, Ye L, Wang X, Li Y, Yang M, Liu S, Hua X, Wen W, Lin C, Long Z, Zhang W, Li H, Jian Y, Zhu Z, Wu X, Lin H. ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer. J Exp Clin Cancer Res 2021; 40:149. [PMID: 33931075 PMCID: PMC8086123 DOI: 10.1186/s13046-021-01932-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/30/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. METHODS In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients' samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. RESULTS ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-β receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. CONCLUSION Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.
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Affiliation(s)
- Xiaoqing Sun
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Zhenyu He
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Ling Guo
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Caiqin Wang
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, People's Republic of China
| | - Chuyong Lin
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Liping Ye
- Department of Experimental Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Xiaoqing Wang
- Department of Radiotherapy, Nanfang Hospital, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Yue Li
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Meisongzhu Yang
- Department of Physiology, Sun Yat-sen University, Guangzhou, 510080, Guangdong, People's Republic of China
| | - Sailan Liu
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Xin Hua
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Wen Wen
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Chao Lin
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Zhiqing Long
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Wenwen Zhang
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Han Li
- Department of Gynecological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Yunting Jian
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Ziyuan Zhu
- Department of General surgery, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou, 510150, Guangdong, People's Republic of China
| | - Xianqiu Wu
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, Guangdong, People's Republic of China.
| | - Huanxin Lin
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China.
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Wang M, Chen W, Chen J, Yuan S, Hu J, Han B, Huang Y, Zhou W. Abnormal saccharides affecting cancer multi-drug resistance (MDR) and the reversal strategies. Eur J Med Chem 2021; 220:113487. [PMID: 33933752 DOI: 10.1016/j.ejmech.2021.113487] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/24/2021] [Accepted: 04/15/2021] [Indexed: 02/07/2023]
Abstract
Clinically, chemotherapy is the mainstay in the treatment of multiple cancers. However, highly adaptable and activated survival signaling pathways of cancer cells readily emerge after long exposure to chemotherapeutics drugs, resulting in multi-drug resistance (MDR) and treatment failure. Recently, growing evidences indicate that the molecular action mechanisms of cancer MDR are closely associated with abnormalities in saccharides. In this review, saccharides affecting cancer MDR development are elaborated and analyzed in terms of aberrant aerobic glycolysis and its related enzymes, abnormal glycan structures and their associated enzymes, and glycoproteins. The reversal strategies including depletion of ATP, circumventing the original MDR pathway, activation by or inhibition of sugar-related enzymes, combination therapy with traditional cytotoxic agents, and direct modification on the sugar moiety, are ultimately proposed. It follows that abnormal saccharides have a significant effect on cancer MDR development, providing a new perspective for overcoming MDR and improving the outcome of chemotherapy.
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Affiliation(s)
- Meizhu Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China
| | - Wenming Chen
- Department of Pharmaceutical Production Center, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China
| | - Jiansheng Chen
- College of Horticulture, South China Agricultural University, 483, Wushan Rd, Guangzhou, Guangdong province, 510642, China
| | - Sisi Yuan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China
| | - Jiliang Hu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China
| | - Bangxing Han
- Department of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, Anhui, China; Anhui Engineering Laboratory for Conservation and Sustainable Utilization of Traditional Chinese Medicine Resources, West Anhui University, Lu'an, Anhui, China
| | - Yahui Huang
- College of Horticulture, South China Agricultural University, 483, Wushan Rd, Guangzhou, Guangdong province, 510642, China.
| | - Wen Zhou
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
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32
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Zhang Y, Zhang L, Iliuk A, Tao WA. Profiling Glycoproteins on Functionalized Reverse Phase Protein Array. Methods Mol Biol 2021; 2237:207-215. [PMID: 33237420 PMCID: PMC12036830 DOI: 10.1007/978-1-0716-1064-0_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Reverse phase protein array (RPPA), a high-throughput, parallel immunoassay in a dot-blot format, is a powerful tool to quantitatively profile protein expression in multiple samples simultaneously using small amounts of material. Despite its success, analysis of post-translationally modified (PTM) proteins has been limited in RPPA assays, primarily due to relatively low availability of antibodies specific to proteins of PTMs, e.g., glycosylation. Moreover, the high matrix complexity, with tens of thousands of proteins in cell lysates or tissue extracts and the low abundance of proteins with PTMs, makes it extremely challenging to detect these proteins with PTMs. Therefore, there is an urgent need to fill this gap, which would greatly contribute to the analysis of a specific PTM by RPPA. In this chapter, we introduce a novel RPPA platform, termed polymer-based reverse phase glycoprotein array (polyGPA), to measure the variation of glycosylation patterns on a three-dimensionally functionalized RPPA. Without the need of specific antibody towards glycosylation, polyGPA represents a highly sensitive strategy to analyze protein glycosylation in multiple complex biological samples in parallel.
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Affiliation(s)
- Ying Zhang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Liyuan Zhang
- Key Laboratory of Proteomics, Dalian Medical University, Dalian, China
| | - Anton Iliuk
- Tymora Analytical Operations, West Lafayette, IN, USA
| | - W Andy Tao
- Tymora Analytical Operations, West Lafayette, IN, USA.
- Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
- Department of Chemistry, Purdue University, West Lafayette, IN, USA.
- Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
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Ma M, Han G, Wang Y, Zhao Z, Guan F, Li X. Role of FUT8 expression in clinicopathology and patient survival for various malignant tumor types: a systematic review and meta-analysis. Aging (Albany NY) 2020; 13:2212-2230. [PMID: 33323540 PMCID: PMC7880376 DOI: 10.18632/aging.202239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/22/2020] [Indexed: 12/28/2022]
Abstract
Dysregulation of α(1,6)-fucosyltransferase (FUT8) plays significant roles in development of a variety of malignant tumor types. We collected as many relevant articles and microarray datasets as possible to assess the prognostic value of FUT8 expression in malignant tumors. For this purpose, we systematically searched PubMed, Embase, Web of Science, Springer, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang, and eventually identified 7 articles and 35 microarray datasets (involving 6124 patients and 10 tumor types) for inclusion in meta-analysis. In each tumor type, FUT8 expression showed significant (p< 0.05) correlation with one or more clinicopathological parameters; these included patient gender, molecular subgroup, histological grade, TNM stage, estrogen receptor, progesterone receptor, and recurrence status. In regard to survival prognosis, FUT8 expression level was associated with overall survival in non-small cell lung cancer (NSCLC), breast cancer, diffuse large B cell lymphoma, gastric cancer, and glioma. FUT8 expression was also correlated with disease-free survival in NSCLC, breast cancer, and colorectal cancer, and with relapse-free survival in pancreatic ductal adenocarcinoma. For most tumor types, survival prognosis of patients with high FUT8 expression was related primarily to clinical features such as gender, tumor stage, age, and pathological category. Our systematic review and meta-analysis confirmed the association of FUT8 with clinicopathological features and patient survival rates for numerous malignant tumor types. Verification of prognostic value of FUT8 in these tumor types will require a large-scale study using standardized methods of detection and analysis.
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Affiliation(s)
- Minxing Ma
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Institute of Hematology, School of Medicine, Northwest University, Xi'an, China.,Department of Oncology, The Fifth People's Hospital of Qinghai Province, Xining, China
| | - Guoxiong Han
- Department of Oncology, The Fifth People's Hospital of Qinghai Province, Xining, China
| | - Yi Wang
- Department of Hematology, Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Ziyan Zhao
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an, China
| | - Feng Guan
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an, China
| | - Xiang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Institute of Hematology, School of Medicine, Northwest University, Xi'an, China.,Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an, China
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Hollenbeck MG, Blevins AA, Gatrone EE, Hundal T, O'Connell K, Lavigne JJ. Identifying Synthetic Lectins from a Competitive Screen for the Detection of Prostate Cancer. Bioconjug Chem 2020; 31:2750-2758. [PMID: 33275847 DOI: 10.1021/acs.bioconjchem.0c00526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Herein, we report a dual dye competitive screening method for the identification of five boronic acid functionalized synthetic lectins (SLs) that are selective for prostate-associated targets with the goal of detecting and staging prostate cancer. This method uses differently labeled normal (RWEP-1) and diseased (PC3) cell membrane extracts in a competitive binding assay to identify SLs that bind either the cancerous or normal extracts but not both. Subsequent studies examined the efficacy of these new SL hits in an array format to discriminate six prostate cell lines. The SL array was able to (a) classify the prostate cell lines with 83% accuracy, (b) discriminate the same cell lines based on their metastatic potential (noncancerous/healthy, cancerous/lowly metastatic, and cancerous/metastatic) with 96% classification accuracy, and (c) exhibit enhanced selectivity for prostate-derived versus colon-derived cell lines. Further analysis delineated the contribution from each SL in these studies, providing a focused SL array having potential utility as a cancer diagnostic.
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Affiliation(s)
- Mary Grace Hollenbeck
- Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
| | - Anna A Blevins
- Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
| | - Erin E Gatrone
- Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
| | - Tanya Hundal
- Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
| | - Kathleen O'Connell
- Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
| | - John J Lavigne
- Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, United States
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Shao P, Wei C, Wang Y. ALG3 contributes to the malignant properties of OSCC cells by regulating CDK-Cyclin pathway. Oral Dis 2020; 27:1426-1434. [PMID: 33084111 DOI: 10.1111/odi.13687] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 10/12/2020] [Accepted: 10/14/2020] [Indexed: 01/08/2023]
Abstract
In this study, we planned to investigate the function and potential mechanisms of Alpha-1,3-mannosyltransferase (ALG3) in oral squamous cell carcinoma (OSCC). Data from TCGA were used to analyze ALG3 expression and its effect on the prognosis of patients with OSCC. KEGG enrichment analysis was applied to explore the pathways related to ALG3. ALG3 expression was measured by qPCR and Western blot. Cell counting kit-8, colony formation, and transwell assays were implemented to detect the effects of ALG3 on malignant biological properties of OSCC cells. The expression of key proteins related to CDK-Cyclin pathway was detected by Western blot. The expression of ALG3 in OSCC samples was higher than that of the control samples, and the increase of ALG3 expression was related to unfavorable prognosis of OSCC patients. Additionally, the elevated expression of ALG3 was associated with pathological stage, lymph node metastasis, and primary lesion in OSCC patients. ALG3 depletion blocked the growth and movement of OSCC cells, while over-expression ALG3 reversed these phenomena. Moreover, exhaustion of ALG3 resulted in decreased expression of MCM7/CCNB2/CDK1/PCNA, while these phenomena were inversed after ALG3 up-regulation. The enhancement of ALG3 expression promoted the aggressive biological behaviors of OSCC cells probably by promoting CDK-Cyclin pathway.
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Affiliation(s)
- Peihong Shao
- Stomatology Wards of Tengzhou Central People's Hospital in Shandong Province, Tengzhou, China
| | - Chengshi Wei
- Stomatology Department, Liaocheng People's Hospital, Liaocheng, China
| | - Yun Wang
- Stomatology Department, Liaocheng People's Hospital, Liaocheng, China
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Hu Y, Pan J, Shah P, Ao M, Thomas SN, Liu Y, Chen L, Schnaubelt M, Clark DJ, Rodriguez H, Boja ES, Hiltke T, Kinsinger CR, Rodland KD, Li QK, Qian J, Zhang Z, Chan DW, Zhang H. Integrated Proteomic and Glycoproteomic Characterization of Human High-Grade Serous Ovarian Carcinoma. Cell Rep 2020; 33:108276. [PMID: 33086064 PMCID: PMC7970828 DOI: 10.1016/j.celrep.2020.108276] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 06/18/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022] Open
Abstract
Many gene products exhibit great structural heterogeneity because of an array of modifications. These modifications are not directly encoded in the genomic template but often affect the functionality of proteins. Protein glycosylation plays a vital role in proper protein functions. However, the analysis of glycoproteins has been challenging compared with other protein modifications, such as phosphorylation. Here, we perform an integrated proteomic and glycoproteomic analysis of 83 prospectively collected high-grade serous ovarian carcinoma (HGSC) and 23 non-tumor tissues. Integration of the expression data from global proteomics and glycoproteomics reveals tumor-specific glycosylation, uncovers different glycosylation associated with three tumor clusters, and identifies glycosylation enzymes that were correlated with the altered glycosylation. In addition to providing a valuable resource, these results provide insights into the potential roles of glycosylation in the pathogenesis of HGSC, with the possibility of distinguishing pathological outcomes of ovarian tumors from non-tumors, as well as classifying tumor clusters.
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Affiliation(s)
- Yingwei Hu
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Jianbo Pan
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Punit Shah
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Minghui Ao
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Stefani N Thomas
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Yang Liu
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Lijun Chen
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Michael Schnaubelt
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - David J Clark
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Emily S Boja
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Tara Hiltke
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Christopher R Kinsinger
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Karin D Rodland
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA
| | - Qing Kay Li
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Jiang Qian
- Department of Ophthalmology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Zhen Zhang
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Daniel W Chan
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
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Kim KH, Lee SY, Kim DG, Lee SY, Kim JY, Yoo JS. Absolute Quantification of N-Glycosylation of Alpha-Fetoprotein Using Parallel Reaction Monitoring with Stable Isotope-Labeled N-Glycopeptide as an Internal Standard. Anal Chem 2020; 92:12588-12595. [PMID: 32786443 DOI: 10.1021/acs.analchem.0c02563] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alpha-fetoprotein (AFP) is a well-established serum biomarker for hepatocellular carcinoma (HCC) in clinical laboratories. However, AFP levels can often be high in benign liver diseases such as liver cirrhosis. For this reason, specifically, the level of the aberrant N-glycosylation of AFP has been proposed as a HCC biomarker to improve diagnostic performance using targeted mass spectrometry (MS). In this study, we developed an endoglycosidase-assisted absolute quantification (AQUA) method by which to measure N-glycosylated AFP levels in serum using liquid chromatography-parallel reaction monitoring with immunoprecipitation. Especially, an isotopically labeled synthetic N-glycopeptide with N-acetylhexosamine (HexNAc) attached to asparagine (N) was used as an internal standard. The efficacy of this method was demonstrated by quantifying the N-glycosylation of AFP in human serum. As a result, we showed that the lower limit of the quantification of a stable isotope-labeled N-glycopeptide reached an attomolar level. Our method also had a linear dynamic range from 2 to 6000 ng/mL for N-glycosylated AFP levels. Finally, the N-glycosylation levels of AFP were measured in HCC patients and in healthy donors with the coefficient of variation in both cases (<10% CV). To the best of our knowledge, this is the first report of the AQUA of N-glycosylated AFP in human sera using a stable isotope-labeled glycopeptide as an internal standard. The results demonstrate that our method can facilitate the discovery and verification of aberrant glycoprotein biomarkers in human serum and plasma through sensitive and precise quantification.
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Affiliation(s)
- Kwang Hoe Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, 162 YeonGuDanji-Ro, Ochang-eup, Cheongju 28119, Republic of Korea
| | - Sang Yoon Lee
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, 162 YeonGuDanji-Ro, Ochang-eup, Cheongju 28119, Republic of Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Dong Geun Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, 162 YeonGuDanji-Ro, Ochang-eup, Cheongju 28119, Republic of Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Soo-Youn Lee
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Jin Young Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, 162 YeonGuDanji-Ro, Ochang-eup, Cheongju 28119, Republic of Korea
| | - Jong Shin Yoo
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, 162 YeonGuDanji-Ro, Ochang-eup, Cheongju 28119, Republic of Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea
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Pérez AG, Andrade-Da-Costa J, De Souza WF, De Souza Ferreira M, Boroni M, De Oliveira IM, Freire-Neto CA, Fernandes PV, De Lanna CA, Souza-Santos PT, Morgado-Díaz JA, De-Freitas-Junior JCM. N‑glycosylation and receptor tyrosine kinase signaling affect claudin‑3 levels in colorectal cancer cells. Oncol Rep 2020; 44:1649-1661. [PMID: 32945502 PMCID: PMC7448416 DOI: 10.3892/or.2020.7727] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 07/14/2020] [Indexed: 12/14/2022] Open
Abstract
Changes in protein levels in different components of the apical junctional complex occur in colorectal cancer (CRC). Claudin-3 is one of the main constituents of tight junctions, and its overexpression can increase the paracellular flux of macromolecules, as well as the malignant potential of CRC cells. The aim of this study was to investigate the molecular mechanisms involved in the regulation of claudin-3 and its prognostic value in CRC. In silico evaluation in each of the CRC consensus molecular subtypes (CMSs) revealed that high expression levels of CLDN3 (gene encoding claudin-3) in CMS2 and CMS3 worsened the patients' long-term survival, whereas a decrease in claudin-3 levels concomitant with a reduction in phosphorylation levels of epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) could be achieved by inhibiting N-glycan biosynthesis in CRC cells. We also observed that specific inactivation of these receptor tyrosine kinases (RTKs) led to a decrease in claudin-3 levels, and this regulation seems to be mediated by phospholipase C (PLC) and signal transducer and activator of transcription 3 (STAT3) in CRC cells. RTKs are modulated by their N-linked glycans, and inhibition of N-glycan biosynthesis decreased the claudin-3 levels; therefore, we evaluated the correlation between N-glycogenes and CLDN3 expression levels in each of the CRC molecular subtypes. The CMS1 (MSI immune) subtype concomitantly exhibited low expression levels of CLDN3 and N-glycogenes (MGAT5, ST6GAL1, and B3GNT8), whereas CMS2 (canonical) exhibited high gene expression levels of CLDN3 and N-glycogenes (ST6GAL1 and B3GNT8). A robust positive correlation was also observed between CLDN3 and B3GNT8 expression levels in all CMSs. These results support the hypothesis of a mechanism integrating RTK signaling and N-glycosylation for the regulation of claudin-3 levels in CRC, and they suggest that CLDN3 expression can be used to predict the prognosis of patients identified as CMS2 or CMS3.
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Affiliation(s)
- Amelia G Pérez
- Cellular and Molecular Oncobiology Program, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Jéssica Andrade-Da-Costa
- Cellular and Molecular Oncobiology Program, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Waldemir F De Souza
- Cellular and Molecular Oncobiology Program, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Michelle De Souza Ferreira
- Cellular and Molecular Oncobiology Program, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Mariana Boroni
- Bioinformatics and Computational Biology Laboratory, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Ivanir M De Oliveira
- Pathology Division, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Carlos A Freire-Neto
- Cellular and Molecular Oncobiology Program, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Priscila V Fernandes
- Pathology Division, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | - Cristóvão A De Lanna
- Bioinformatics and Computational Biology Laboratory, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
| | | | - José A Morgado-Díaz
- Cellular and Molecular Oncobiology Program, National Cancer Institute (INCA), Rio de Janeiro, RJ 20231‑050, Brazil
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Franconetti A, López Ó, Fernandez-Bolanos JG. Carbohydrates: Potential Sweet Tools Against Cancer. Curr Med Chem 2020; 27:1206-1242. [DOI: 10.2174/0929867325666180719114150] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 04/25/2018] [Accepted: 06/28/2018] [Indexed: 12/13/2022]
Abstract
:Cancer, one of the most devastating degenerative diseases nowadays, is one of the main targets in Medicinal Chemistry and Pharmaceutical industry. Due to the significant increase in the incidence of cancer within world population, together with the complexity of such disease, featured with a multifactorial nature, access to new drugs targeting different biological targets connected to cancer is highly necessary.:Among the vast arsenal of compounds exhibiting antitumor activities, this review will cover the use of carbohydrate derivatives as privileged scaffolds. Their hydrophilic nature, together with their capacity of establishing selective interactions with biological receptors located on cell surface, involved in cell-to-cell communication processes, has allowed the development of an ample number of new templates useful in cancer treatment.:Their intrinsic water solubility has allowed their use as of pro-drug carriers for accessing more efficiently the pharmaceutical targets. The preparation of glycoconjugates in which the carbohydrate is tethered to a pharmacophore has also allowed a better permeation of the drug through cellular membranes, in which selective interactions with the carbohydrate motifs are involved. In this context, the design of multivalent structures (e.g. gold nanoparticles) has been demonstrated to enhance crucial interactions with biological receptors like lectins, glycoproteins that can be involved in cancer progression.:Moreover, the modification of the carbohydrate structural motif, by incorporation of metal complexes, or by replacing their endocyclic oxygen, or carbon atoms with heteroatoms has led to new antitumor agents.:Such diversity of sugar-based templates with relevant antitumor activity will be covered in this review.
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Affiliation(s)
- Antonio Franconetti
- Departamento de Quimica Organica, Facultad de Quimica, Universidad de Sevilla, Sevilla, Spain
| | - Óscar López
- Departamento de Quimica Organica, Facultad de Quimica, Universidad de Sevilla, Sevilla, Spain
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Li LX, Zhang B, Gong RZ. Insights into the role of tumor abnormal protein in early diagnosis of cancer: A prospective cohort study. Medicine (Baltimore) 2020; 99:e19382. [PMID: 32176062 PMCID: PMC7220304 DOI: 10.1097/md.0000000000019382] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The aim of this study was to evaluate the clinical use of tumor abnormal protein (TAP) in the diagnosis of different cancers.Totally 394 patients were divided into 4 groups, namely 100 healthy volunteers, 167 patients with cancer, 20 subjects with precancerous lesions, and 107 subjects with benign lesions. TAP was detected in 4 groups of research subjects using a TAP testing kit and examination system. We correlated TAP levels with a wide variety of clinical indicators as well as established cancer markers, including alpha fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9). Besides, the changes of TAP level in 51 patients with liver cancer before and after surgery, and overall survival of patients with high or low TAP expression in pancreatic, gallbladder, bile duct, and liver cancers were analyzed.Statistically significant difference was observed in the TAP-positive ratio among subjects with cancer (79.6%) and precancerous lesions (45.0%) compared to the healthy volunteers (4.0%). TAP expression in different cancers was characterized by high sensitivity (79.64%), specificity (89.87%), positive and negative predictive value (85.25% and 85.71%), overall compliance rate (85.53%) but low omission and mistake diagnostic rate (20.36% and 10.13%), Youden index (0.6951). In addition, there was no significant difference among patients with different types of cancer (χ = 2.886, P = .410), and TAP expression was shown to be correlated with AFP in liver cancer (P = .034) but not with CA19-9 in pancreatic cancer (P = .241). Moreover, the overall survival of patients with low expression of TAP in pancreatic, gallbladder, bile duct, and liver cancers were significantly higher than of patients with high expression of TAP. Compared with the preoperative patients with cancer, TAP levels decreased dramatically among postoperative subjects (P < .001).In summary, TAP might hold promise in serving as universal indicator for the diagnosis of different cancers.
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Affiliation(s)
- Lu-Xi Li
- Department of Ophthalmology, Xi’an No 3 Hospital, The Affiliated Hospital of Northwest University
| | - Bin Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Air Force Medical University
| | - Rui-Zhi Gong
- Department of Oncology, Xi’an International Medical Center, Xi’an, Shaanxi, China
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Plant lectins and their usage in preparing targeted nanovaccines for cancer immunotherapy. Semin Cancer Biol 2020; 80:87-106. [PMID: 32068087 DOI: 10.1016/j.semcancer.2020.02.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/30/2020] [Accepted: 02/06/2020] [Indexed: 01/06/2023]
Abstract
Plant lectins, a natural source of glycans with a therapeutic potential may lead to the discovery of new targeted therapies. Glycans extracted from plant lectins are known to act as ligands for C-type lectin receptors (CLRs) that are primarily present on immune cells. Plant-derived glycosylated lectins offer diversity in their N-linked oligosaccharide structures that can serve as a unique source of homogenous and heterogenous glycans. Among the plant lectins-derived glycan motifs, Man9GlcNAc2Asn exhibits high-affinity interactions with CLRs that may resemble glycan motifs of pathogens. Thus, such glycan domains when presented along with antigens complexed with a nanocarrier of choice may bewilder the immune cells and direct antigen cross-presentation - a cytotoxic T lymphocyte immune response mediated by CD8+ T cells. Glycan structure analysis has attracted considerable interest as glycans are looked upon as better therapeutic alternatives than monoclonal antibodies due to their cost-effectiveness, reduced toxicity and side effects, and high specificity. Furthermore, this approach will be useful to understand whether the multivalent glycan presentation on the surface of nanocarriers can overcome the low-affinity lectin-ligand interaction and thereby modulation of CLR-dependent immune response. Besides this, understanding how the heterogeneity of glycan structure impacts the antigen cross-presentation is pivotal to develop alternative targeted therapies. In the present review, we discuss the findings on structural analysis of glycans from natural lectins performed using GlycanBuilder2 - a software tool based on a thorough literature review of natural lectins. Additionally, we discuss how multiple parameters like the orientation of glycan ligands, ligand density, simultaneous targeting of multiple CLRs and design of antigen delivery nanocarriers may influence the CLR targeting efficacy. Integrating this information will eventually set the ground for new generation immunotherapeutic vaccine design for the treatment of various human malignancies.
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Osada Y, Ito C, Nishiyama-Fujita Y, Ogura S, Sakurai A, Akimoto M, Aisa Y, Nakazato T. Prognostic Impact of ABO Blood Group on Survival in Patients With Malignant Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:122-129. [DOI: 10.1016/j.clml.2019.09.607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/09/2019] [Accepted: 09/21/2019] [Indexed: 11/26/2022]
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Pang B, Zhu Y, Ni J, Thompson J, Malouf D, Bucci J, Graham P, Li Y. Extracellular vesicles: the next generation of biomarkers for liquid biopsy-based prostate cancer diagnosis. Theranostics 2020; 10:2309-2326. [PMID: 32089744 PMCID: PMC7019149 DOI: 10.7150/thno.39486] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 10/01/2019] [Indexed: 12/13/2022] Open
Abstract
Prostate cancer (PCa) is a leading cause of cancer death for males in western countries. The current gold standard for PCa diagnosis - template needle biopsies - often does not convey a true representation of the molecular profile given sampling error and complex tumour heterogeneity. Presently available biomarker blood tests have limited accuracy. There is a growing demand for novel diagnostic approaches to reduce both the number of men with an abnormal PSA/ DRE who undergo invasive biopsy and the number of cores collected per biopsy. 'Liquid biopsy' is a minimally invasive biofluid-based approach that has the potential to provide information and improve the accuracy of diagnosis for patients' treatment selection, prognostic counselling and development of risk-adjusted follow-up protocols. Extracellular vesicles (EVs) are lipid bilayer-delimited particles released by tumour cells which may provide a real-time snapshot of the entire tumour in a non-invasive way. EVs can regulate physiological processes and mediate systemic dissemination of various types of cancers. Emerging evidence suggests that EVs have crucial roles in PCa development and metastasis. Most importantly, EVs are directly derived from their parent cells with their information. EVs contain components including proteins, mRNAs, DNA fragments, non-coding RNAs and lipids, and play a critical role in intercellular communication. Therefore, EVs hold promise for the discovery of liquid biopsy-based biomarkers for PCa diagnosis. Here, we review the current approaches for EV isolation and analysis, summarise the recent advances in EV protein biomarkers in PCa and focus on liquid biopsy-based EV biomarkers in PCa diagnosis for personalised medicine.
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Affiliation(s)
- Bairen Pang
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
- Cancer Care Centre, St. George Hospital, Sydney, NSW 2217, Australia
| | - Ying Zhu
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
- Cancer Care Centre, St. George Hospital, Sydney, NSW 2217, Australia
| | - Jie Ni
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
- Cancer Care Centre, St. George Hospital, Sydney, NSW 2217, Australia
| | - James Thompson
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
- Department of Urology, St George Hospital, Sydney, NSW 2217, Australia
- Garvan Institute of Medical Research/ APCRC, Sydney, UNSW, 2010, Australia
| | - David Malouf
- Cancer Care Centre, St. George Hospital, Sydney, NSW 2217, Australia
- Department of Urology, St George Hospital, Sydney, NSW 2217, Australia
| | - Joseph Bucci
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
- Cancer Care Centre, St. George Hospital, Sydney, NSW 2217, Australia
| | - Peter Graham
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
- Cancer Care Centre, St. George Hospital, Sydney, NSW 2217, Australia
| | - Yong Li
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
- Cancer Care Centre, St. George Hospital, Sydney, NSW 2217, Australia
- School of Basic Medical Sciences, Zhengzhou University, Henan 450001, China
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Integrated Transcriptomics, Proteomics, and Glycomics Reveals the Association between Up-regulation of Sialylated N-glycans/Integrin and Breast Cancer Brain Metastasis. Sci Rep 2019; 9:17361. [PMID: 31758065 PMCID: PMC6874669 DOI: 10.1038/s41598-019-53984-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 11/07/2019] [Indexed: 12/21/2022] Open
Abstract
Breast cancer brain metastasis has been recognized as one of the central issues in breast cancer research. The elucidation of the processes and pathways that mediate this step will provide important clues for a better understanding of breast cancer metastasis. Increasing evidence suggests that aberrant glycosylation patterns greatly contribute to cell invasion and cancer metastasis. Herein, we combined next-generation RNA sequencing with liquid chromatography-tandem mass spectrometry-based proteomic and N-glycomic analysis from five breast cancer cell lines and one brain cancer cell line to investigate the possible mechanisms of breast cancer brain metastasis. The genes/proteins associated with cell movement were highlighted in breast cancer brain metastasis. The integrin signaling pathway and the up-regulation of α-integrin (ITGA2, ITGA3) were associated with the brain metastatic process. 12 glycogenes showed unique expression in 231BR, which could result in an increase of sialylation during brain metastasis. In agreement with the changes of glycogenes, 60 out of 63 N-glycans that were identified exhibited differential expression among cell lines. The correlation between glycogenes and glycans revealed the importance of sialylation and sialylated glycans in breast cancer brain metastasis. Highly sialylated N-glycans, which were up-regulated in brain-seeking cell line 231BR, likely play a role in brain metastasis.
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Tommasone S, Allabush F, Tagger YK, Norman J, Köpf M, Tucker JHR, Mendes PM. The challenges of glycan recognition with natural and artificial receptors. Chem Soc Rev 2019; 48:5488-5505. [PMID: 31552920 DOI: 10.1039/c8cs00768c] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Glycans - simple or complex carbohydrates - play key roles as recognition determinants and modulators of numerous physiological and pathological processes. Thus, many biotechnological, diagnostic and therapeutic opportunities abound for molecular recognition entities that can bind glycans with high selectivity and affinity. This review begins with an overview of the current biologically and synthetically derived glycan-binding scaffolds that include antibodies, lectins, aptamers and boronic acid-based entities. It is followed by a more detailed discussion on various aspects of their generation, structure and recognition properties. It serves as the basis for highlighting recent key developments and technical challenges that must be overcome in order to fully deal with the specific recognition of a highly diverse and complex range of glycan structures.
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Affiliation(s)
- Stefano Tommasone
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
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46
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Dong X, Peng W, Yu CY, Zhou S, Donohoo KB, Tang H, Mechref Y. 8-plex LC-MS/MS Analysis of Permethylated N-Glycans Achieved by Using Stable Isotopic Iodomethane. Anal Chem 2019; 91:11794-11802. [PMID: 31356052 PMCID: PMC7412976 DOI: 10.1021/acs.analchem.9b02411] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Glycosylation is an important post-translational modification of proteins. Many diseases, such as cancer, have proved to be related to aberrant glycosylation. High throughput quantitative methods have gained attention recently in the study of glycomics. With the development of high-resolution mass spectrometry, the sensitivity of detection in glycomics has largely improved; however, most of the commonly used MS-based techniques are focused on relative quantitative analysis, which can hardly provide direct comparative glycomic quantitation results. In this study, we developed a novel multiplex glycomic analysis method on an LC-ESI-MS platform. Reduced glycans were stable isotopic labeled during the permethylation procedure, with the use of iodomethane reagents CH2DI, CHD2I, CD3I, 13CH3I, 13CH2DI, 13CHD2I, 13CD3I, and CH3I. Up to 8-plex glycomic profiling was possible in a single analysis by LC-MS, and a 100 k mass resolution was sufficient to allow a baseline resolution of the mass differences among the 8-plex labeled glycans. The major advantages of this method are that it overcomes quantitative fluctuations caused by nanoESI, it facilitates a level of comparative quantitative glycomic analysis that accurately reflects the quantitative information in samples, and it dramatically shortens analysis time. Quantitation validation was tested on glycans released from bovine fetuin and model glycoprotein mixtures (RNase B, bovine fetuin, and IgG) with good linearity (R2 = 0.9884) and a dynamic range from 0.1 to 10. The 8-plex strategy was successfully applied to a comparative glycomic study of cancer cell lines. The results demonstrate that different distributions of sialylated glycans are related to the metastatic properties of cell lines and provide important clues for a better understanding of breast cancer brain metastasis.
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Affiliation(s)
- Xue Dong
- Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas, 79409, United States
| | - Wenjing Peng
- Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas, 79409, United States
| | - Chuan-Yih Yu
- School of Informatics & Computing, Indiana University, Bloomington, Indiana, 47408, United States
| | - Shiyue Zhou
- Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas, 79409, United States
| | - Kaitlyn B. Donohoo
- Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas, 79409, United States
| | - Haixu Tang
- School of Informatics & Computing, Indiana University, Bloomington, Indiana, 47408, United States
| | - Yehia Mechref
- Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas, 79409, United States
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47
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Evaluation of AGP Fucosylation as a Marker for Hepatocellular Carcinoma of Three Different Etiologies. Sci Rep 2019; 9:11580. [PMID: 31399619 PMCID: PMC6689003 DOI: 10.1038/s41598-019-48043-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 07/26/2019] [Indexed: 02/08/2023] Open
Abstract
A mass spectrometric analysis platform has been developed to determine whether glycosylation patterns of alpha-1 acid glycoprotein (AGP) could be used as a marker for early detection of hepatocellular carcinoma (HCC) in different etiologies, i.e. non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALC), and hepatitis C virus (HCV). MALDI-MS profiling of N-glycans of AGP purified from 20 μL of patient serum in HCC (n = 72) and liver cirrhosis (n = 58) showed that a unique trifucosylated tetra-antennary glycan (m/z 3490.76) was predominantly identified in HCCs but was absent in healthy subjects and the majority of cirrhosis patients. Receiver operation characteristic (ROC) curve analysis showed that the trifucosylated N-glycan of AGP (triFc_AGP) could differentiate HCC from cirrhosis with an area under the curve (AUC) of 0.707, 0.726 and 0.751 for NASH, ALC and HCV, respectively. When combining triFc_AGP with INR and AFP, the panel had the greatest benefit in detection of NASH-related HCCs, with a significantly improved AUC of 0.882 for all NASH HCCs and 0.818 for early NASH HCCs compared to AFP alone (0.761 and 0.641, respectively). Moreover, triFc_AGP could serve as a potential marker for monitoring AFP-negative HCC patients.
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48
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Black AP, Liang H, West CA, Wang M, Herrera HP, Haab BB, Angel PM, Drake RR, Mehta AS. A Novel Mass Spectrometry Platform for Multiplexed N-Glycoprotein Biomarker Discovery from Patient Biofluids by Antibody Panel Based N-Glycan Imaging. Anal Chem 2019; 91:8429-8435. [PMID: 31177770 DOI: 10.1021/acs.analchem.9b01445] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A new platform for N-glycoprotein analysis from serum that combines matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) workflows with antibody slide arrays is described. Antibody panel based (APB) N-glycan imaging allows for the specific capture of N-glycoproteins by antibodies on glass slides and N-glycan analysis in a protein-specific and multiplexed manner. Development of this technique has focused on characterizing two abundant and well-studied human serum glycoproteins, alpha-1-antitrypsin and immunoglobulin G. Using purified standard solutions and 1 μL samples of human serum, both glycoproteins can be immunocaptured and followed by enzymatic release of N-glycans. N-Glycans are detected with a MALDI FT-ICR mass spectrometer in a concentration-dependent manner while maintaining specificity of capture. Importantly, the N-glycans detected via slide-based antibody capture were identical to that of direct analysis of the spotted standards. As a proof of concept, this workflow was applied to patient serum samples from individuals with liver cirrhosis to accurately detect a characteristic increase in an IgG N-glycan. This novel approach to protein-specific N-glycan analysis from an antibody panel can be further expanded to include any glycoprotein for which a validated antibody exists. Additionally, this platform can be adapted for analysis of any biofluid or biological sample that can be analyzed by antibody arrays.
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Affiliation(s)
- Alyson P Black
- Department of Cell and Molecular Pharmacology , Medical University of South Carolina , 173 Ashley Avenue, BSB 310 , Charleston , South Carolina 29425 , United States
| | - Hongyan Liang
- Department of Cell and Molecular Pharmacology , Medical University of South Carolina , 173 Ashley Avenue, BSB 310 , Charleston , South Carolina 29425 , United States
| | - Connor A West
- Department of Cell and Molecular Pharmacology , Medical University of South Carolina , 173 Ashley Avenue, BSB 310 , Charleston , South Carolina 29425 , United States
| | - Mengjun Wang
- Department of Cell and Molecular Pharmacology , Medical University of South Carolina , 173 Ashley Avenue, BSB 310 , Charleston , South Carolina 29425 , United States
| | - Harmin P Herrera
- Department of Microbiology and Immunology , Drexel University College of Medicine , 2900 Queen Lane , Philadephia , Pennsylvania 19129 , United States
| | - Brian B Haab
- Van Andel Research Institute , 333 Bostwick Ave. , Grand Rapids , Michigan 49503 , United States
| | - Peggi M Angel
- Department of Cell and Molecular Pharmacology , Medical University of South Carolina , 173 Ashley Avenue, BSB 310 , Charleston , South Carolina 29425 , United States
| | - Richard R Drake
- Department of Cell and Molecular Pharmacology , Medical University of South Carolina , 173 Ashley Avenue, BSB 310 , Charleston , South Carolina 29425 , United States
| | - Anand S Mehta
- Department of Cell and Molecular Pharmacology , Medical University of South Carolina , 173 Ashley Avenue, BSB 310 , Charleston , South Carolina 29425 , United States
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Zhu J, Warner E, Parikh ND, Lubman DM. Glycoproteomic markers of hepatocellular carcinoma-mass spectrometry based approaches. MASS SPECTROMETRY REVIEWS 2019; 38:265-290. [PMID: 30472795 PMCID: PMC6535140 DOI: 10.1002/mas.21583] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 10/19/2018] [Indexed: 05/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third most-common cause of cancer-related death worldwide. Most cases of HCC develop in patients that already have liver cirrhosis and have been recommended for surveillance for an early onset of HCC. Cirrhosis is the final common pathway for several etiologies of liver disease, including hepatitis B and C, alcohol, and increasingly non-alcoholic fatty liver disease. Only 20-30% of patients with HCC are eligible for curative therapy due primarily to inadequate early-detection strategies. Reliable, accurate biomarkers for HCC early detection provide the highest likelihood of curative therapy and survival; however, current early-detection methods that use abdominal ultrasound and serum alpha fetoprotein are inadequate due to poor adherence and limited sensitivity and specificity. There is an urgent need for convenient and highly accurate validated biomarkers for HCC early detection. The theme of this review is the development of new methods to discover glycoprotein-based markers for detection of HCC with mass spectrometry approaches. We outline the non-mass spectrometry based methods that have been used to discover HCC markers including immunoassays, capillary electrophoresis, 2-D gel electrophoresis, and lectin-FLISA assays. We describe the development and results of mass spectrometry-based assays for glycan screening based on either MALDI-MS or ESI analysis. These analyses might be based on the glycan content of serum or on glycan screening for target molecules from serum. We describe some of the specific markers that have been developed as a result, including for proteins such as Haptoglobin, Hemopexin, Kininogen, and others. We discuss the potential role for other technologies, including PGC chromatography and ion mobility, to separate isoforms of glycan markers. Analyses of glycopeptides based on new technologies and innovative softwares are described and also their potential role in discovery of markers of HCC. These technologies include new fragmentation methods such as EThcD and stepped HCD, which can identify large numbers of glycopeptide structures from serum. The key role of lectin extraction in various assays for intact glycopeptides or their truncated versions is also described, where various core-fucosylated and hyperfucosylated glycopeptides have been identified as potential markers of HCC. Finally, we describe the role of LC-MRMs or lectin-FLISA MRMs as a means to validate these glycoprotein markers from patient samples. These technological advancements in mass spectrometry have the potential to lead to novel biomarkers to improve the early detection of HCC.
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Affiliation(s)
- Jianhui Zhu
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
| | - Elisa Warner
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
| | - Neehar D. Parikh
- Department of Internal Medicine, The University of Michigan, Ann Arbor 48109, Michigan
| | - David M. Lubman
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
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50
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Li D, Liang L, Tang Y, Fu L, Xiao S, Yuan Q. Direct and single-step sensing of primary ovarian cancers related glycosidases. CHINESE CHEM LETT 2019. [DOI: 10.1016/j.cclet.2018.12.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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