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dc.creatorFreitas, D
dc.creatorCampos, D
dc.creatorGomes, J
dc.creatorPinto, F
dc.creatorMacedo, JA
dc.creatorMatos, R
dc.creatorMereiter, S
dc.creatorPinto, MT
dc.creatorPolónia, A
dc.creatorGärtner, F
dc.creatorMagalhães, A
dc.creatorReis, CA
dc.description.abstractBackground: Changes in glycosylation are known to play critical roles during gastric carcinogenesis. Expression of truncated O-glycans, such as the Sialyl-Tn (STn) antigen, is a common feature shared by many cancers and is associated with cancer aggressiveness and poor-prognosis. Methods: Glycoengineered cell lines were used to evaluate the impact of truncated O-glycans in cancer cell biology using in vitro functional assays, transcriptomic analysis and in vivo models. Tumor patients ‘samples and datasets were used for clinical translational significance evaluation. Findings: In the present study, we demonstrated that gastric cancer cells expressing truncated O-glycans display major phenotypic alterations associated with higher cell motility and cell invasion. Noteworthy, the glycoengineered cancer cells overexpressing STn resulted in tumor xenografts with less cohesive features which had a critical impact on mice survival. Furthermore, truncation of O-glycans induced activation of EGFR and ErbB2 receptors and a transcriptomic signature switch of gastric cancer cells. The disclosed top activated genes were further validated in gastric tumors, revealing that SRPX2 and RUNX1 are concomitantly overexpressed in gastric carcinomas and its expression is associated with patients’ poor-survival, highlighting their prognosis potential in clinical practice. Interpretation: This study discloses novel molecular links between O-glycans truncation frequently observed in cancer and key cellular regulators with major impact in tumor progression and patients’ clinical outcome.
dc.description.sponsorshipThis work was funded by FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE ( POCI-01-0145-FEDER-016585 ; POCI-01-0145-FEDER-007274 ; POCI-01-0145-FEDER-028489 ) and National Funds through the Foundation for Science and Technology (FCT) , under the projects: PTDC/BBB-EBI/0567/2014 (to CAR), PTDC/MED-ONC/28489/2017 (to AM) and UID/BIM/04293/2013 ; and the project NORTE-01-0145-FEDER-000029 , supported by Norte Portugal Regional Programme ( NORTE 2020 ), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). The authors acknowledge the support by Gastric Glyco Explorer Initial Training Network (European Union Seventh Framework Programme GastricGlycoExplorer project, grant number 316929 ). DF acknowledges the FCT PhD Programmes and Programa Operacional Potencial Humano (POPH), specifically the BiotechHealth Programe (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences), with the reference PD/0016/2012 funded by FCT . Grants were received from FCT, POPH and FSE (Fundo Social Europeu): SFRH/BD/110636/2015 to DF and SFRH/BPD/115730/2016 to FP. We thank Catharina Steentoft and Henrik Clausen for the cell line models and helpful scientific discussions. We are grateful for Nuno Mendes's technical support. The authors acknowledge the support of José Luis Costa and Mafalda Rocha from the i3S Genomics Platform (GenCore), and Maria G Lazaro from the Bioimaging I3S Scientific Platform , member of the PPBI ( PPBI-POCI-01-0145-FEDER-022122 ).
dc.relation.ispartofEBioMedicine, vol.40, p. 349-362
dc.subjectGastric cancer
dc.subject.meshCell Line, Tumor
dc.subject.meshComputational Biology / methods
dc.subject.meshDisease Models, Animal
dc.subject.meshDisease Progression
dc.subject.meshGene Expression Profiling
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshNeoplasm Invasiveness
dc.subject.meshPolysaccharides / metabolism
dc.subject.meshProtein-Tyrosine Kinases / metabolismo
dc.subject.meshSignal Transduction
dc.subject.meshStomach Neoplasms / genetics
dc.subject.meshStomach Neoplasms / metabolism
dc.subject.meshStomach Neoplasms / mortality
dc.subject.meshStomach Neoplasms / pathology
dc.subject.meshTranscription, Genetic
dc.titleO-glycans truncation modulates gastric cancer cell signaling and transcription leading to a more aggressive phenotype
dc.typeArtigo em Revista Científica Internacional
dc.contributor.uportoInstituto de Investigação e Inovação em Saúde
Appears in Collections:I3S - Artigo em Revista Científica Internacional

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