Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/10216/119042 |
Resumo: | Background Terminal a2-3 and a2-6 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 a2-6 towards a2-3 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. |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancerGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticGlycomicsHumansLewis X Antigen/biosynthesisLewis X Antigen/geneticsNeoplasm Proteins/biosynthesisNeoplasm Proteins/geneticsPolysaccharides/biosynthesisPolysaccharides/geneticsReceptor Protein-Tyrosine Kinases/geneticsReceptor Protein-Tyrosine Kinases/metabolismSialyltransferases/biosynthesisSialyltransferases/geneticsStomachNeoplasms/geneticsStomach Neoplasms/metabolismBackground Terminal a2-3 and a2-6 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 a2-6 towards a2-3 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.Elsevier20162016-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10216/119042eng0304-416510.1016/j.bbagen.2015.12.016Mereiter, SMagalhães, AAdamczyk, BJin, CAlmeida, ADrici, LIbáñez-Vea, MGomes, CFerreira, JAAfonso, LSantos, LLarsen, MKolarich, DKarlsson, NReis, CAinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T14:19:58Zoai:repositorio-aberto.up.pt:10216/119042Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T23:59:07.699766Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer |
title |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer |
spellingShingle |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer Mereiter, S Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Glycomics Humans Lewis X Antigen/biosynthesis Lewis X Antigen/genetics Neoplasm Proteins/biosynthesis Neoplasm Proteins/genetics Polysaccharides/biosynthesis Polysaccharides/genetics Receptor Protein-Tyrosine Kinases/genetics Receptor Protein-Tyrosine Kinases/metabolism Sialyltransferases/biosynthesis Sialyltransferases/genetics Stomach Neoplasms/genetics Stomach Neoplasms/metabolism |
title_short |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer |
title_full |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer |
title_fullStr |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer |
title_full_unstemmed |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer |
title_sort |
Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer |
author |
Mereiter, S |
author_facet |
Mereiter, S Magalhães, A Adamczyk, B Jin, C Almeida, A Drici, L Ibáñez-Vea, M Gomes, C Ferreira, JA Afonso, L Santos, L Larsen, M Kolarich, D Karlsson, N Reis, CA |
author_role |
author |
author2 |
Magalhães, A Adamczyk, B Jin, C Almeida, A Drici, L Ibáñez-Vea, M Gomes, C Ferreira, JA Afonso, L Santos, L Larsen, M Kolarich, D Karlsson, N Reis, CA |
author2_role |
author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Mereiter, S Magalhães, A Adamczyk, B Jin, C Almeida, A Drici, L Ibáñez-Vea, M Gomes, C Ferreira, JA Afonso, L Santos, L Larsen, M Kolarich, D Karlsson, N Reis, CA |
dc.subject.por.fl_str_mv |
Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Glycomics Humans Lewis X Antigen/biosynthesis Lewis X Antigen/genetics Neoplasm Proteins/biosynthesis Neoplasm Proteins/genetics Polysaccharides/biosynthesis Polysaccharides/genetics Receptor Protein-Tyrosine Kinases/genetics Receptor Protein-Tyrosine Kinases/metabolism Sialyltransferases/biosynthesis Sialyltransferases/genetics Stomach Neoplasms/genetics Stomach Neoplasms/metabolism |
topic |
Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Glycomics Humans Lewis X Antigen/biosynthesis Lewis X Antigen/genetics Neoplasm Proteins/biosynthesis Neoplasm Proteins/genetics Polysaccharides/biosynthesis Polysaccharides/genetics Receptor Protein-Tyrosine Kinases/genetics Receptor Protein-Tyrosine Kinases/metabolism Sialyltransferases/biosynthesis Sialyltransferases/genetics Stomach Neoplasms/genetics Stomach Neoplasms/metabolism |
description |
Background Terminal a2-3 and a2-6 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 a2-6 towards a2-3 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. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016 2016-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/10216/119042 |
url |
https://hdl.handle.net/10216/119042 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0304-4165 10.1016/j.bbagen.2015.12.016 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799135914333569025 |