Decreased expression of the adhesion molecule desmoglein-2 is associated with diffuse-type gastric carcinoma

doi:10.1016/j.ejca.2006.03.024

European Journal of Cancer

Volume 42, Issue 14, September 2006, Pages 2397-2403

https://doi.org/10.1016/j.ejca.2006.03.024 Get rights and content

Abstract

Desmoglein-2 (Dsg2) is one of the components of the cell–cell adherence junction. We previously reported that loss of heterozygosity at chromosome 18q12, on which the Dsg2 gene exists, is frequently found in diffuse-type gastric cancers. This study investigated the relationship between Dsg2 expression and diffuse-type gastric cancers. A total of 112 primary tumours resected from patients with gastric cancer were stained with a monoclonal antibody against Dsg2 and examined for correlations between the expression of Dsg2 and various clinicopathological factors, including loss of heterozygosity on chromosome 18q and prognosis. Dsg2 is immunolocalised at cell–cell boundaries in normal gastric mucosa. Loss of Dsg2 expression was observed in 33 of 112 gastric tumours. There was a statistically significant correlation between a decrease in Dsg2 staining and loss of tumour differentiation (P < 0.001), tumour macroscopic feature (P < 0.001) and peritoneal dissemination (P = 0.023), and Dsg2-negative staining was correlated significantly with loss of heterozygosity on chromosome 18q12 (P = 0.001). The prognosis of patients with Dsg2-negative tumours was significantly worse than that of those with Dsg2-positive tumours (log rank, P < 0.01), while multivariate analysis revealed that Dsg2 was not an independent prognostic factor. These findings suggest that decreased expression of Dsg2 is associated with diffuse-type gastric cancers and poor prognosis in gastric carcinoma.

Introduction

Epithelial cell–cell adhesion is important in tumour development. Two adhering-type junctions, the desmosome and adherens junctions, are responsible for strong cell–cell adhesion. Each of these junctions consists of a transmembrane cadherin and a complex cytoplasmic plaque that serve to link cadherin to actin microfilaments or the intermediate filament cytoskeleton.¹ Intercellular junctions known as desmosomes are multimolecular membrane domains that provide intercellular adhesion and membrane anchors for the intermediate filament cytoskeleton.² Desmosomes contain the desmosomal cadherins, desmogleins (Dsgs) and desmocollins that are linked to the intermediate filament cytoskeleton through interactions with plakoglobin and desmoplakin.1, 3, 4 The adherens junction is composed of a classic cadherin (e.g. E-, P- or N-cadherin) linked to β-catenin or plakoglobin.5, 6 Thus, plakoglobin is found in both adherens junctions and desmosomes, while β-catenin is restricted to the adherens junction.1, 7, 8 Alpha-catenin links the cadherin/catenin complex to the actin cytoskeleton through interactions with β-actinin, vinculin, ZO-1 and actin filaments.9, 10 Lost or reduced plakoglobin expression has been observed in tumour tissues and metastatic lesions, and has been linked to poor prognosis in a variety of tumours.¹¹

Dsgs are transmembrane glycoproteins of the desmosome, a cell–cell adhesive structure prominent in epithelial tissues,¹² which have been reported to be associated with tumour development.² cDNA and protein studies have revealed that there are subfamilies of Dsgs (types 1, 2 and 3) and desmocollins (types 1, 2 and 3).¹³ Type 2 Dsg (Dsg2), but not type 1 or 3, is expressed in stomach epithelia.¹⁴ We previously reported that loss of heterozygosity (LOH) on chromosome 18q12 in diffuse-type gastric cancer is significantly higher than in intestinal-type gastric cancer, and we suggested that Dsg2, which exists at 18q12, might be a candidate tumour suppressor locus in diffuse-type gastric cancers.¹⁵

Gastric cancers have been classified into two histological types: intestinal-type and diffuse-type. Diffuse-type gastric cancers show decreased cell–cell adhesion, which is associated with metastatic potential. These histological features indicate that a decrease in adhesive junctions may be involved in the emergence of diffuse-type gastric cancers. A decrease in E-cadherin has been reported to be one cause of the decrease in adhesive junctions, but not all diffuse-type gastric cancers show such a decrease.16, 17 Although Dsg2 may play an important role in the carcinogenesis of gastric cancer, to the best of our knowledge, there is only one report in the literature on Dsg2 and gastric cancer.¹⁸ In the present study, we investigated the relationship between Dsg2 expression and clinicopathological characteristics in gastric cancer.

Section snippets

Clinical materials

A total of 112 patients who had undergone resection of a primary gastric tumour at our institute between 1988 and 1996, and who were histologically confirmed to have sporadic advanced gastric cancer were enrolled in the present study. Advanced cancer was defined as cancer invasion into the muscularis propria or serosa. Tumour specimens were fixed in 10% formaldehyde solution v/v and embedded in paraffin. Sections 4 μm thick were cut and mounted on glass slides. The pathological diagnoses and

Desmoglein-2 and E-cadherin expression in gastric cancer

Dsg2 and E-cadherin were primarily immunolocalised at cell–cell boundaries, and to some extent in the cytoplasm in normal gastric mucosa. The expression of both Dsg2 and E-cadherin was observed at cell–cell boundaries in an intestinal-type carcinoma. Differential expression levels between Dsg2 and E-cadherin were found in cancer cells. Decreased expression of Dsg2 was observed in some lesions with normal expression of E-cadherin, and decreased expression of E-cadherin was also found in some

Discussion

In the present study, Dsg2 expression was found to be significantly decreased in diffuse-type gastric carcinoma, indicating that the loss of Dsg2 correlates with differentiation in gastric carcinomas. It has been suggested that desmosomal components may underlie differentiation in human endometrial carcinoma and murine squamous carcinoma.20, 21 Biedermann and colleagues have also reported that abnormal expression of Dsg2 is involved in the carcinogenesis of diffuse-type gastric carcinomas.¹⁸

Conflict of interest statement

None declared.

Acknowledgement

This study was supported in part by a Grant-in Aid for Scientific Research (C) 13671329 and (B) 13470260 from the Ministry of Education, Science, Sports, Culture and Technology of Japan, the Japan Health Sciences Foundation, and by a Grant-in Aid for the Osaka City University Medical Research Foundation.

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Decreased expression of the adhesion molecule desmoglein-2 is associated with diffuse-type gastric carcinoma

Abstract

Introduction

Section snippets

Clinical materials

Desmoglein-2 and E-cadherin expression in gastric cancer

Discussion

Conflict of interest statement

Acknowledgement

Semin Cell Biol

Curr Opin Cell Biol

Am J Pathol

Oral Oncol

J Biol Chem

Cancer Lett

The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for desmoglein 2

J Cell Sci

Desmosomal adhesion inhibits invasive behavior

Proc Natl Acad Sci USA

Assembly of the cadherin-catenin complex in vitro with recombinant proteins

J Cell Sci

Genetic and biochemical dissection of protein linkages in the cadherin-catenin complex

Proc Natl Acad Sci USA

Identification of amino acid sequence motifs in desmocollin, a desmosomal glycoprotein, that are required for plakoglobin binding and plaque formation

Proc Natl Acad Sci USA

Plakoglobin domains that define its association with the desmosomal cadherins and the classical cadherins: identification of unique and shared domains

J Cell Sci

Functional domains of alpha-catenin required for the strong state of cadherin-based cell adhesion

J Cell Biol

alpha-Catenin-vinculin interaction functions to organize the apical junctional complex in epithelial cells

J Cell Biol

Molecular interactions between desmosomal cadherins

Biochem J