Effect of tumor-associated mutant E-cadherin variants with defects in exons 8 or 9 on matrix metalloproteinase 3
✍ Scribed by Margit Fuchs; Christine Hermannstädter; Katja Specht; Pjotr Knyazev; Axel Ullrich; Erika Rosivatz; Raymonde Busch; Peter Hutzler; Heinz Höfler; Birgit Luber
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 285 KB
- Volume
- 202
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. The cell adhesion molecule E‐cadherin is frequently down‐regulated or mutated in tumors. In addition to down‐regulation of cell adhesion, degradation of the extracellular matrix by matrix metalloproteinases is necessary for tumor cell spread. To investigate a possible link between E‐cadherin and matrix metalloproteinase 3 (MMP‐3), we examined expression of MMP‐3 in human MDA‐MB‐435S cells transfected with wild‐type (wt) or three different tumor‐associated mutant E‐cadherin variants with alterations in exons 8 or 9, originally identified in gastric carcinoma patients. In the presence of wt E‐cadherin, the MMP‐3 protein level was decreased in cellular lysates and in the supernatant where a secreted form of the protein is detectable. Down‐regulation of MMP‐3 was not found in MDA‐MB‐435S transfectants expressing mutant E‐cadherin variants which indicates that E‐cadherin mutations interfere with the MMP‐3 suppressing function of E‐cadherin. The mechanism of regulation of MMP‐3 by E‐cadherin is presently not clear. We have previously found that cell motility is enhanced by expression of the mutant E‐cadherin variants used in this study. Here, we found that application of the synthetic inhibitor of MMP‐3 NNGH and small interfering RNA (siRNA) directed against MMP‐3 reduce mutant E‐cadherin‐enhanced cell motility. Taken together, our results point to a functional link between MMP‐3 and E‐cadherin. MMP‐3 is differentially regulated by expression of wt or mutant E‐cadherin. On the other hand, MMP‐3 plays a role in the enhancement of cell motility by mutant E‐cadherin. Both observations may be highly relevant for tumor progression since they concern degradation of the extracellular matrix and tumor cell spread. © 2004 Wiley‐Liss, Inc.