Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer

Stefan Mereiter, Ana Magalhães, Barbara Adamczyk, Chunsheng Jin, Andreia Almeida, Lylia Drici, Maria Ibáñez-Vea, Catarina Gomes, José A Ferreira, Luis P Afonso, Lúcio L Santos, Martin R Larsen, Daniel Kolarich, Niclas G Karlsson, Celso A Reis

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND: Terminal α2-3 and α2-6 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 α2-6 towards α2-3 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.

OriginalsprogEngelsk
TidsskriftBBA Reviews on Cancer
Vol/bind1860
Udgave nummer8
Sider (fra-til)1795-1808
ISSN0304-419X
DOI
StatusUdgivet - aug. 2016

Fingeraftryk

Neoplasms
Glycosylation
Sialyltransferases
Precision Medicine
Antigen Receptors
rice bran saccharide
Insulin Receptor
Integrins
Liquid Chromatography
Ligation
Proteins
Cell Line

Citer dette

Mereiter, Stefan ; Magalhães, Ana ; Adamczyk, Barbara ; Jin, Chunsheng ; Almeida, Andreia ; Drici, Lylia ; Ibáñez-Vea, Maria ; Gomes, Catarina ; Ferreira, José A ; Afonso, Luis P ; Santos, Lúcio L ; Larsen, Martin R ; Kolarich, Daniel ; Karlsson, Niclas G ; Reis, Celso A. / Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer. I: BBA Reviews on Cancer. 2016 ; Bind 1860, Nr. 8. s. 1795-1808.
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title = "Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer",
abstract = "BACKGROUND: Terminal α2-3 and α2-6 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 α2-6 towards α2-3 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.",
keywords = "Antigens, CD15, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Glycomics, Humans, Neoplasm Proteins, Polysaccharides, Receptor Protein-Tyrosine Kinases, Sialyltransferases, Stomach Neoplasms, Journal Article, Research Support, Non-U.S. Gov't",
author = "Stefan Mereiter and Ana Magalh{\~a}es and Barbara Adamczyk and Chunsheng Jin and Andreia Almeida and Lylia Drici and Maria Ib{\'a}{\~n}ez-Vea and Catarina Gomes and Ferreira, {Jos{\'e} A} and Afonso, {Luis P} and Santos, {L{\'u}cio L} and Larsen, {Martin R} and Daniel Kolarich and Karlsson, {Niclas G} and Reis, {Celso A}",
note = "Copyright {\circledC} 2015 Elsevier B.V. All rights reserved.",
year = "2016",
month = "8",
doi = "10.1016/j.bbagen.2015.12.016",
language = "English",
volume = "1860",
pages = "1795--1808",
journal = "B B A - Reviews on Cancer",
issn = "0304-419X",
publisher = "Elsevier",
number = "8",

}

Mereiter, S, Magalhães, A, Adamczyk, B, Jin, C, Almeida, A, Drici, L, Ibáñez-Vea, M, Gomes, C, Ferreira, JA, Afonso, LP, Santos, LL, Larsen, MR, Kolarich, D, Karlsson, NG & Reis, CA 2016, 'Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer', BBA Reviews on Cancer, bind 1860, nr. 8, s. 1795-1808. https://doi.org/10.1016/j.bbagen.2015.12.016

Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer. / Mereiter, Stefan; Magalhães, Ana; Adamczyk, Barbara; Jin, Chunsheng; Almeida, Andreia; Drici, Lylia; Ibáñez-Vea, Maria; Gomes, Catarina; Ferreira, José A; Afonso, Luis P; Santos, Lúcio L; Larsen, Martin R; Kolarich, Daniel; Karlsson, Niclas G; Reis, Celso A.

I: BBA Reviews on Cancer, Bind 1860, Nr. 8, 08.2016, s. 1795-1808.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer

AU - Mereiter, Stefan

AU - Magalhães, Ana

AU - Adamczyk, Barbara

AU - Jin, Chunsheng

AU - Almeida, Andreia

AU - Drici, Lylia

AU - Ibáñez-Vea, Maria

AU - Gomes, Catarina

AU - Ferreira, José A

AU - Afonso, Luis P

AU - Santos, Lúcio L

AU - Larsen, Martin R

AU - Kolarich, Daniel

AU - Karlsson, Niclas G

AU - Reis, Celso A

N1 - Copyright © 2015 Elsevier B.V. All rights reserved.

PY - 2016/8

Y1 - 2016/8

N2 - BACKGROUND: Terminal α2-3 and α2-6 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 α2-6 towards α2-3 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.

AB - BACKGROUND: Terminal α2-3 and α2-6 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 α2-6 towards α2-3 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.

KW - Antigens, CD15

KW - Gene Expression Regulation, Enzymologic

KW - Gene Expression Regulation, Neoplastic

KW - Glycomics

KW - Humans

KW - Neoplasm Proteins

KW - Polysaccharides

KW - Receptor Protein-Tyrosine Kinases

KW - Sialyltransferases

KW - Stomach Neoplasms

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.bbagen.2015.12.016

DO - 10.1016/j.bbagen.2015.12.016

M3 - Journal article

C2 - 26721331

VL - 1860

SP - 1795

EP - 1808

JO - B B A - Reviews on Cancer

JF - B B A - Reviews on Cancer

SN - 0304-419X

IS - 8

ER -