Salomé Pinho (Ipatimup) distinguida pela EACR com o «Young investigator Award»

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Salomé Pinho (Ipatimup) distinguida pela EACR com o «Young investigator Award»

Salomé Pinho (IPATIMUP) distinguida pela EACR com o «Young investigator Award»
Sexta, 04.01.2013

Salomé Pinho was awarded with the “Young Investigator Award” by the EACR for her contribution for the identification of a novel regulatory system of a protein that is determinant in the process of gastric cancer development and progression.

This work was recently published in Biochimica et Biophysica Acta (Pinho SS et al BBA 2012 [Epub ahead of print]) and PLoS ONE (Pinho SS et al. PLoS One. 2012;7(3):e33191) journals.


Abstract

N-acetylglucosaminyltransferases III and V regulate E-cadherin stability at the cell membrane. Implications in the Epithelial to Mesenchymal Transition.
Salomé S. Pinhoa,b, Sandra Carvalhoa, Joana Cabrala, Joana Figueiredoa, Patricia Oliveiraa, Fátima Gärtnerab, Tomoya Isajic, Jianguo Guc, Fátima Carneiroa,d,e, Raquel Serucaa,d, Naoyuki Taniguchif, Carla Oliveiraa,d, Celso A. Reisa,b,d

a Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal
b Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, Largo Prof. Abel Salazar, 2, 4099-003 Porto, Portugal
c Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi 981-8558, Japan
d Medical Faculty, University of Porto, Alameda Prof. Hernâni Monteiro 4200-319 Porto, Portugal
e Department of Pathology, Hospital S. João, Alameda Prof. Hernâni Monteiro 4200-319 Porto, Portugal
f Systems Glycobiology Research Group, RIKEN Advanced Science Institute, 2-1 Hirosawa Wako, Saitama 351-0198, Japan

E-cadherin is a cell-cell adhesion molecule whose dysfunction or inactivation is a common feature of invasive carcinomas. In addition, E-cadherin is a well-accepted marker of phenotypic plasticity, and is a central molecule during Epithelial to Mesenchymal Transition (EMT) signaling pathway, that occurs during embryonic development, tissue regeneration, and thought to occur in cancer initiation/progression. The post-translational regulation by N-glycosylation through GnT-III and GnT-V glycosyltransferases has been reported by others and us to be an alternative mechanism of E-cadherin functional regulation. We have demonstrated that GnT-III induced a stabilizing effect on E-cadherin at the cell membrane by inducing a delay in the turnover rate of the protein which promotes the formation of stable and functional adherens-junction, and further prevents clathrin-dependent E-cadherin endocytosis. This contributes to E-cadherin-mediated tumor invasion suppression function. Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization together with formation of unstable adherens-junctions and impairment of cell-cell adhesion, therefore contributing to tumor progression. This stabilizer/destabilizer effect of GnT-III and GnT-V on E-cadherin was further validated in clinical samples of human invasive carcinomas. Furthermore, we also found that during Epithelial to Mesenchymal Transition (EMT), Mgat3 expression was dramatically decreased and later recovered when cells returned to an epithelial-like phenotype (Mesenchymal to Epithelial Transition (MET)). We further identified that Mgat3 promoter methylation/demethylation is a mechanism involved in this expression regulation. The impact of Mgat3/GnT-III expression variation, along EMT/MET, was accompanied with a specific modification of E-cadherin glycosylation with bisecting GlcNAc structures. These results open new insights into the molecular mechanisms associated with the regulation of E-cadherin in tumor cells with potential translational clinical and therapeutic applications. In addition, we have identified for the first time Mgat3 glycogene expression and GnT-III-mediated glycosylation, specifically on E-cadherin, as a novel and major component of the EMT/MET mechanism signature, supporting its role during EMT/MET.