Abstract
BackgroundThe E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression.MethodsWe studied the alterations of E-cadherin and β-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC).ResultsA high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and β-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for β-catenin IHC. An association was found between reduced expression of E-cadherin and β-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype.ConclusionOur results support the hypothesis that alterations of E-cadherin and β-catenin play a role in the initiation and progression of gastric cancer.
Highlights
The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture
The findings above indicated that the E-cadherin gene is a tumour-suppressor gene because it is in accordance with the classical two-hit theory for tumour suppressor genes [30]
In cell line MKN45 mentioned above with weak cell-cell adhesion, a 12-bp in frame deletion of E-cadherin gene and loss of the wild type allele were detected [29]. This cell line still showed strong expression of mRNAs and proteins, suggesting that reduced expression and structural abnormalities themselves may result in inactivation of the E-cadherin-mediated cell adhesion system [29]
Summary
The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. E-cadherin (120 kDa; chromosome 16q) is a classical cadherin and forms the key functional component of adherence junctions between epithelial cells [1]. It is bound via a series of undercoat proteins, the catenins (α, β and γ) to the actin cytoskeleton [1]. An intact E-cadherin – catenin complex is required for maintenance of normal intercellular adhesion. E-cadherin and catenin staining is strong in well-differentiated cancers that maintain their cell adhesiveness and are less invasive, but is reduced in poorly-differentiated tumours which have lost their cell-cell adhesion and show strong invasive behaviour [2,3]
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