Alterações de glicosilação: um novo mecanismo de ativação de vias oncogénicas

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Alterações de glicosilação: um novo mecanismo de ativação de vias oncogénicas

Sexta, 22.07.2016

A expressão de antigénios sialilados, como o silayl Lewis X (SLeX), está associada a tumores mais agressivos com pior prognóstico. Neste estudo, publicado na revista Biochimica et Biophysica Acta, foi utilizada uma linha celular gástrica com sobre expressão de uma enzima envolvida na biossíntese do antigénio SLeX, a glicosiltransferase ST3GalIV. Foram avaliadas a nível estrutural as alterações do perfil de O- e N-glicosilação deste modelo celular e foi possível identificar 47 proteínas com um aumento significativo de N-glicanos sialilados. Este grupo de proteínas com glicosilação alterada incluí várias proteínas associadas à carcinogénese gástrica, nomeadamente a proteína tirosina cinase recetora RON. Demonstramos neste modelo que o recetor RON se encontra modificado com SLeX e a sua concomitante ativação. A co expressão de RON e SLeX foi validada em amostras clínicas de tumores gástricos, revelando um mecanismo alternativo de ativação de vias oncogénicas dependente da glicosilação. Este estudo foi desenvolvido no âmbito de uma rede Marie Curie, Gastric Glyco Explorer (GGE), financiada pela União Europeia.

 

Autores e Afiliações:

Stefan Mereiter a,b,c, Ana Magalhães a,b, Barbara Adamczyk d, Chunsheng Jin d, Andreia Almeida e,f, Lylia Drici g,Maria Ibáñez-Vea g, Catarina Gomes a,b, José A. Ferreira a,b,h, Luis P. Afonso i, Lúcio L. Santos h,j, Martin R. Larsen g, Daniel Kolarich e, Niclas G. Karlsson d, Celso A. Reis a,b,c,k

a i3S — Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal

b Institute of Molecular Pathology and Immunology of the University of Porto — IPATIMUP, Porto, Portugal

c Institute of Biomedical Sciences of Abel Salazar — ICBAS, University of Porto, Portugal

d Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden

e Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany

f Free University Berlin, Berlin, Germany

g Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

h Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology of Porto, Portugal

i Department of Pathology, Portuguese Institute of Oncology of Porto, Portugal

j Department of Surgical Oncology, Portuguese Institute of Oncology of Porto, Portugal

k Medical Faculty, University of Porto, Portugal

 

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 (SLeX). SLeX 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 SLeX and the concomitant activation. SLeX 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.

 

Revista: Biochimica et Biophysica Acta (BBA) - General Subjects

 

Link: http://www.sciencedirect.com/science/article/pii/S0304416515003554