Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1860, Issue 8, Pages 1795-1808Publisher
ELSEVIER
DOI: 10.1016/j.bbagen.2015.12.016
Keywords
ST3GAL4; Sialyl Lewis X (SLeX); RON; Gastric cancer; Glycome; Sialome
Categories
Funding
- European Union [316929]
- FCT, the Portuguese Foundation for Science and Technology
- FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE [FCOMP-01-0124-FEDER028188]
- National Funds through the FCT-Foundation for Science and Technology [PEst-C/SAU/LA0003/2013, PTDC/BBB-EBI/0786/2012, PTDC/BBB-EBI/0567/2014]
- Glycoproteomics project [PCIG09-GA-2011-293847]
- Danish Natural Science Research Council
- VILLUM Foundation
- FCT
- POPH (Programa Operational Potential Humano)
- FSE (Fundo Social Europeu) [SFRH/BPD/75871/2011, SFRH/BPD/111048/2015, SFRH/BPD/96510/2013]
- Ingabritt and Arne Lundbergs Research Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Research Council [342-2004-4434]
- Villum Fonden [00007292] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [PTDC/BBB-EBI/0567/2014, PEst-C/SAU/LA0003/2013, PTDC/BBB-EBI/0786/2012, SFRH/BPD/111048/2015] Funding Source: FCT
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Background: Terminal alpha 2-3 and alpha 2-6 sialylation of glycans precludes further chain elongation, leading to the biosynthesis of cancer relevant epitopes such as sialyl-Lewis X (SLe(X)). SLe(X) overexpression is associated with tumor aggressive phenotype and patients' poor prognosis. Methods: MKN45 gastric carcinoma cells transfected with the sialyltransferase ST3GAL4 were established as a model overexpressing sialylated terminal glycans. We have evaluated at the structural level the glycome and the sialoproteome of this gastric cancer cell line applying liquid chromatography and mass spectrometry. We further validated an identified target expression by proximity ligation assay in gastric tumors. Results: Our results showed that ST3GAL4 overexpression leads to several glycosylation alterations, including reduced O-glycan extension and decreased bisected and increased branched N-glycans. A shift from alpha 2-6 towards alpha 2-3 linked sialylated N-glycans was also observed. Sialoproteomic analysis further identified 47 proteins with significantly increased sialylated N-glycans. These included integrins, insulin receptor, carcinoembryonic antigens and RON receptor tyrosine kinase, which are proteins known to be key players in malignancy. Further analysis of RON confirmed its modification with SLe(X) and the concomitant activation. SLe(X) and RON co-expression was validated in gastric tumors. Conclusion: The overexpression of ST3GAL4 interferes with the overall glycophenotype of cancer cells affecting a multitude of key proteins involved in malignancy. Aberrant glycosylation of the RON receptor was shown as an alternative mechanism of oncogenic activation. General significance: This study provides novel targets and points to an integrative tumor glycomic/proteomic-profiling for gastric cancer patients' stratification. This article is part of a Special Issue entitled Glycans in personalised medicine Guest Editor: Professor Gordan Lauc. (C) 2015 Elsevier B.V. All rights reserved.
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