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.

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.

• Authors: Salomé S Pinho, Joana Figueiredo, Joana Cabral, Sandra Carvalho, Joana Dourado, Ana Magalhães, Fátima Gärtner, Ana Maria Mendonfa, Tomoya Isaji, Jianguo Gu, Fátima Carneiro, Raquel Seruca, Naoyuki Taniguchi, Celso A Reis
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1830 Issue 3 Pg. 2690-700 (Mar 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23671930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Glycosaminoglycans
• N-Acetylglucosaminyltransferases
• beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase
• alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase

Topics

• Adherens Junctions (genetics, metabolism)
• Cadherins (genetics, metabolism)
• Carcinoma (genetics, metabolism, pathology)
• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• Endocytosis
• Gene Expression Regulation, Neoplastic
• Glycosaminoglycans (metabolism)
• Humans
• Kinetics
• N-Acetylglucosaminyltransferases (genetics, metabolism)
• Neoplasm Invasiveness
• Signal Transduction
• Stomach Neoplasms (genetics, metabolism, pathology)