title: E-cadherin and adherens-junctions stability in gastric carcinoma: functional implications of glycosyltransferases involving N-glycan branching biosynthesis, N-acetylglucosaminyltransferases III and V.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal.
authors.forename: Salomé S
authors.initials: SS
authors.lastname: Pinho
authors.forename: Joana
authors.initials: J
authors.lastname: Figueiredo
authors.forename: Joana
authors.initials: J
authors.lastname: Cabral
authors.forename: Sandra
authors.initials: S
authors.lastname: Carvalho
authors.forename: Joana
authors.initials: J
authors.lastname: Dourado
authors.forename: Ana
authors.initials: A
authors.lastname: Magalhães
authors.forename: Fátima
authors.initials: F
authors.lastname: Gärtner
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Mendonfa
authors.forename: Tomoya
authors.initials: T
authors.lastname: Isaji
authors.forename: Jianguo
authors.initials: J
authors.lastname: Gu
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Celso A
authors.initials: CA
authors.lastname: Reis
mesh_terms: D022005:Adherens Junctions / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004705:Endocytosis; D015972:Gene Expression Regulation, Neoplastic; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D015820:Cadherins; D006025:Glycosaminoglycans; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase