BACKGROUND: E-cadherin is a cell-cell adhesion molecule and the dysfunction of which is a common feature of more than 70% of all invasive carcinomas, including gastric cancer. Mechanisms behind the loss of E-cadherin function in gastric carcinomas include mutations and silencing at either the DNA or RNA level. Nevertheless, in a high percentage of gastric carcinoma cases displaying E-cadherin dysfunction, the mechanism responsible for E-cadherin dysregulation is unknown. We have previously demonstrated the existence of a bi-directional cross-talk between E-cadherin and two major N-glycan processing enzymes, N-acetylglucosaminyltransferase-III or -V (GnT-III or GnT-V). METHODS: In the present study, we have characterized the functional implications of the N-glycans catalyzed by GnT-III and GnT-V on the regulation of E-cadherin biological functions and in the molecular assembly and stability of adherens-junctions in a gastric cancer model. The results were validated in human gastric carcinoma samples. RESULTS: We 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, contributing for the formation of stable and functional adherens-junctions, and further preventing clathrin-dependent E-cadherin endocytosis. Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization and unstable adherens-junctions with impairment of cell-cell adhesion. CONCLUSIONS: This supports the role of GnT-III on E-cadherin-mediated tumor suppression, and GnT-V on E-cadherin-mediated tumor invasion. GENERAL SIGNIFICANCE: These results contribute to fill the gap of knowledge of those human carcinoma cases harboring E-cadherin dysfunction, opening new insights into the molecular mechanisms underlying E-cadherin regulation in gastric cancer with potential translational clinical applications.
BACKGROUND:E-cadherin is a cell-cell adhesion molecule and the dysfunction of which is a common feature of more than 70% of all invasive carcinomas, including gastric cancer. Mechanisms behind the loss of E-cadherin function in gastric carcinomas include mutations and silencing at either the DNA or RNA level. Nevertheless, in a high percentage of gastric carcinoma cases displaying E-cadherin dysfunction, the mechanism responsible for E-cadherin dysregulation is unknown. We have previously demonstrated the existence of a bi-directional cross-talk between E-cadherin and two major N-glycan processing enzymes, N-acetylglucosaminyltransferase-III or -V (GnT-III or GnT-V). METHODS: In the present study, we have characterized the functional implications of the N-glycans catalyzed by GnT-III and GnT-V on the regulation of E-cadherin biological functions and in the molecular assembly and stability of adherens-junctions in a gastric cancer model. The results were validated in humangastric carcinoma samples. RESULTS: We 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, contributing for the formation of stable and functional adherens-junctions, and further preventing clathrin-dependent E-cadherin endocytosis. Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization and unstable adherens-junctions with impairment of cell-cell adhesion. CONCLUSIONS: This supports the role of GnT-III on E-cadherin-mediated tumor suppression, and GnT-V on E-cadherin-mediated tumor invasion. GENERAL SIGNIFICANCE: These results contribute to fill the gap of knowledge of those humancarcinoma cases harboring E-cadherin dysfunction, opening new insights into the molecular mechanisms underlying E-cadherin regulation in gastric cancer with potential translational clinical applications.
Authors: S Carvalho; T A Catarino; A M Dias; M Kato; A Almeida; B Hessling; J Figueiredo; F Gärtner; J M Sanches; T Ruppert; E Miyoshi; M Pierce; F Carneiro; D Kolarich; R Seruca; Y Yamaguchi; N Taniguchi; C A Reis; S S Pinho Journal: Oncogene Date: 2015-07-20 Impact factor: 9.867
Authors: Ana M Dias; Alexandra Correia; Márcia S Pereira; Catarina R Almeida; Inês Alves; Vanda Pinto; Telmo A Catarino; Nuno Mendes; Magdalena Leander; M Teresa Oliva-Teles; Luís Maia; Cristina Delerue-Matos; Naoyuki Taniguchi; Margarida Lima; Isabel Pedroto; Ricardo Marcos-Pinto; Paula Lago; Celso A Reis; Manuel Vilanova; Salomé S Pinho Journal: Proc Natl Acad Sci U S A Date: 2018-05-02 Impact factor: 11.205
Authors: Antônio Felix da Silva Filho; Gabriela Souto Vieira-de-Mello; Petra Barros Dos Santos; Moacyr Jesus Barreto de Melo Rêgo; Alfredo Ribeiro-Silva; Eduardo Isidoro Carneiro Beltrão Journal: Pathol Oncol Res Date: 2019-01-28 Impact factor: 3.201