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Nucleolin-Sle A Glycoforms as E-Selectin Ligands and Potentially Targetable Biomarkers at the Cell Surface of Gastric Cancer Cells

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Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal
2
Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
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Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
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Institute for Biomedical Engineering (INEB), Porto, Portugal, 4200-135 Porto, Portugal
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Digestive Cancer Research Group, 1495-161 Algés, Portugal
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REQUIMTE-LAQV, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
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REQUIMTE-LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences of the University of Porto, 4169-007 Porto, Portugal
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Pathology Department, Portuguese Institute of Oncology of Porto, 4200-162 Porto, Portugal
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Immunology Department, Portuguese Institute of Oncology of Porto, 4200-162 Porto, Portugal
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Health Science Faculty, University of Fernando Pessoa, 4249-004 Porto, Portugal
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Department of Surgical Oncology, Portuguese Institute of Oncology of Porto, 4200-162 Porto, Portugal
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Department, Porto Comprehensive Cancer Centre (P.ccc), 4200-162 Porto, Portugal
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cancers 2020, 12(4), 861; https://doi.org/10.3390/cancers12040861
Received: 20 February 2020 / Revised: 24 March 2020 / Accepted: 28 March 2020 / Published: 2 April 2020
Background: Gastric cancer (GC) is a major health burden worldwide, with half of patients developing metastases within 5 years after treatment, urging novel biomarkers for diagnosis and efficient therapeutic targeting. Sialyl-Lewis A (SLeA), a terminal glycoepitope of glycoproteins and glycolipids, offers tremendous potential towards this objective. It is rarely expressed in healthy tissues and blood cells, while it is present in highly metastatic cell lines and metastases. SLeA is also involved in E-selectin mediated metastasis, making it an ideal target to control disease dissemination. Methods and Results: To improve cancer specificity, we have explored the SLeA-glycoproteome of six GC cell models, with emphasis on glycoproteins showing affinity for E-selectin. A novel bioinformatics-assisted algorithm identified nucleolin (NCL), a nuclear protein, as a potential targetable biomarker potentially involved in metastasis. Several immunoassays, including Western blot and in situ proximity ligation reinforced the existence of cell surface NCL-SLeA glycoforms in GC. The NCL-SLeA glycophenotype was associated with decreased survival and was not reflected in relevant healthy tissues. Conclusions: NCL-SLeA is a biomarker of poor prognosis in GC holding potential for precise cancer targeting. This is the first report describing SLeA in preferentially nuclear protein, setting a new paradigm for cancer biomarkers discovery and targeted therapies. View Full-Text
Keywords: gastric cancer; glycomics; glycoproteomics; cancer biomarkers; Sialyl-Lewis A; nucleolin; glycosylation; cancer neoantigens; prognosis biomarkers; precision oncology gastric cancer; glycomics; glycoproteomics; cancer biomarkers; Sialyl-Lewis A; nucleolin; glycosylation; cancer neoantigens; prognosis biomarkers; precision oncology
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MDPI and ACS Style

Fernandes, E.; Freitas, R.; Ferreira, D.; Soares, J.; Azevedo, R.; Gaiteiro, C.; Peixoto, A.; Oliveira, S.; Cotton, S.; Relvas-Santos, M.; Afonso, L.P.; Palmeira, C.; Oliveira, M.J.; Ferreira, R.; Silva, A.M.N.; Lara Santos, L.; Ferreira, J.A. Nucleolin-Sle A Glycoforms as E-Selectin Ligands and Potentially Targetable Biomarkers at the Cell Surface of Gastric Cancer Cells. Cancers 2020, 12, 861. https://doi.org/10.3390/cancers12040861

AMA Style

Fernandes E, Freitas R, Ferreira D, Soares J, Azevedo R, Gaiteiro C, Peixoto A, Oliveira S, Cotton S, Relvas-Santos M, Afonso LP, Palmeira C, Oliveira MJ, Ferreira R, Silva AMN, Lara Santos L, Ferreira JA. Nucleolin-Sle A Glycoforms as E-Selectin Ligands and Potentially Targetable Biomarkers at the Cell Surface of Gastric Cancer Cells. Cancers. 2020; 12(4):861. https://doi.org/10.3390/cancers12040861

Chicago/Turabian Style

Fernandes, Elisabete, Rui Freitas, Dylan Ferreira, Janine Soares, Rita Azevedo, Cristiana Gaiteiro, Andreia Peixoto, Sara Oliveira, Sofia Cotton, Marta Relvas-Santos, Luis P. Afonso, Carlos Palmeira, Maria J. Oliveira, Rita Ferreira, André M.N. Silva, Lúcio Lara Santos, and José A. Ferreira 2020. "Nucleolin-Sle A Glycoforms as E-Selectin Ligands and Potentially Targetable Biomarkers at the Cell Surface of Gastric Cancer Cells" Cancers 12, no. 4: 861. https://doi.org/10.3390/cancers12040861

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