E-cadherin In Gastric Cancer Research Articles

E-cadherin expression – Significance in gastric carcinoma

Gastric carcinoma is aggressive cancer with poor prognosis. E-cadherin is 120 kD calcium mediated transmembrane glycoprotein that forms the cell adhesion molecule which maintains the integrity of epithelial cells by keeping it cohesive. E-cadherin down regulation in gastric cancer is of great significance in the dissociation of epithelial cells, alteration of tumor microenvironment, invasion, tumor genesis and metastasis. To study the E-cadherin expression in gastric carcinoma and to correlate with the existing clinical and pathological parameters.The study included 100 confirmed cases of adenocarcinoma from gastrectomy specimens. Immunostaining was done with E-cadherin mouse monoclonal antibody and expression studied based on the staining pattern and correlated with various clinico-pathological parameters. Data was statistically analysed by chi square test with calculation of p-value.E-cadherin expression showed aberrant staining in 87% cases. E-cadherin expression showed significant correlation with histological types, tumor grade, tumor depth of invasion, lymphovascular invasion and lymphnode involvement. The expression E-cadherin in gastric cancer was aberrant in 100 % of diffuse type and poorly differentiated tumors. 96.61% of lymph node positive cases showed aberrant expression. The cases with aberrant expression were comparatively more in T3 (100%) and T4 (93.75%) tumors.The study highlights the significance of E-cadherin expression in gastric carcinoma that can be utilised as a potent bio marker for aggressiveness, metastasis and prognosis.

Combined high NEDD9 expression and E-cadherin loss correlate with poor clinical outcome in gastric cancer.

Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a member of the Cas family. Previous studies have revealed that NEDD9 coordinates the focal adhesion kinase and Src signaling cascades that are involved in integrin-dependent adhesion and migration, invasion, cell apoptosis and life cycle, and survival, which may play a role in epithelial-mesenchymal transformation. The aim of this study was to analyze the expression of NEDD9 and E-cadherin in gastric cancer (GC) and evaluate their clinical significance. NEDD9 and E-cadherin expression was analyzed with immunohistochemistry using tissue microarray technique in 435 GC patients who underwent gastrectomy. The NEDD9 expression level was defined by the combination score, which was determined by multiplying the staining intensity score and the proportion score (≥5; NEDD9-high, <5; NEDD9-low). E-cadherin loss was defined as a total loss of staining. The clinicopathologic parameters, overall survival, and disease-free survival rates were analyzed according to the NEDD9 and E-cadherin expression status. The combined NEDD9 and E-cadherin expression status correlated with lymphatic invasion (P=0.001), vascular invasion (P=0.020), and T stage (P=0.001). Combined high NEDD9 expression and loss of E-cadherin expression status had a worse overall survival rate (P<0.001) and served as a poor prognostic factor (Hazard ratio 2.49, 95% CI 1.25-5, P=0.01). Immunohistochemical staining for NEDD9 and E-cadherin may function as a candidate prognostic marker for gastric cancer in everyday practice, especially when applied in combination.

Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications.

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human CDH1 gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. After proteolysis, the extracellular fragment of the full-length E-cadhein is released into the extracellular environment and the blood, which is called soluble E-cadherin (sE-cadherin). sE-cadherin promots invasion and metastasis as a paracrine/autocrine signaling molecule in the progression of various types of cancer including gastric cancer. This review mainly summarizes the dysregulation of E-cadherin and the regulatory roles in the progression, invasion, metastasis, and drug-resistance, as well as its clinical applications in diagnosis, prognosis, and therapeutics of gastric cancer.

Association of CDH1 -160 C → A and -347 G→ GA polymorphisms and expression of E-cadherin and gastric cancer: A case-control study.

The loss of function of the E-cadherin (CDH1) gene with -160 C→A and -347 G→GA polymorphisms is regarded as a critical step for gastric cancer. It was aimed to investigate possible association of these polymorphisms and immunoexpression of E-cadherin with gastric cancer. Gastric adenocarcinoma patients and individuals with benign gastric pathologies were included in this case-control study. Demographic data and pathological findings were recorded. Immunohistochemical staining of E-cadherin expression and analysis of -160 C→A and -347 G→GA polymorphisms were done. Differences between allele frequencies of -160 C→A and -347 G→GA polymorphisms and expression of E-cadherin were the primary outcomes. There were 78 gastric cancer patients (Group A) and 113 individuals with benign gastric pathologies (Group B). The number of male patients and mean age were higher in Group A (p <0.001). -160 C→A and 347 G→GA polymorphisms and their allelic distributions showed no difference between the groups (p> 0.05 for all). There was a significant association between -160 C→A polymorphism and grade of E-cadherin expression (p= 0.013). There were no significant differences between survival rates with -160 C→A, 347 G→GA and intensity of E-cadherin expression (p> 0.05 for all). There was no significant association between -160 C→A and -347 G→GA polymorphisms and gastric cancer. There was no impact of E-cadherin expression on tumoral features and survival in gastric cancer. -160 C→A polymorphism may influence the expression of E-cadherin in gastric cancer.

Protocadherin 7 inhibits cell migration and invasion through E-cadherin in gastric cancer.

The protocadherin 7 is a member of the protocadherin family that expressed aberrantly in many types of human cancers. However, its expression, function, and underlying mechanisms are little known in gastric cancer. In this study, we detected protocadherin 7 expression in gastric cancer tissues and non-tumorous gastric mucosa tissues by real-time quantitative polymerase chain reaction and immunohistochemistry. The association of protocadherin 7 expression with the clinicopathological characteristics and the prognosis was subsequently analyzed. MTS ((3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)) and transwell assays were performed to assess the effect of protocadherin 7 on proliferation, migration, and invasion in gastric cancer cell lines. Moreover, real-time quantitative polymerase chain reaction and western blot were used to detect the expression of epithelial-mesenchymal transition markers. Protocadherin 7 expression was decreased gradiently from normal tissue to gastric cancer, especially in gastric cancer tissue with lymph node metastasis. Low expression of protocadherin 7 was significantly associated with Lauren's classification ( p = 0.0005), lymph node metastases ( p = 0.0002), and tumor node metastasis stage ( p = 0.0221), as well as poor prognosis ( p < 0.05). Furthermore, down-regulation of protocadherin 7 in gastric cancer cell lines significantly increased their migration and invasion abilities (both p < 0.05), while it had no influence on the gastric cancer cell proliferation ( p > 0.05). Additionally, our results demonstrated that E-cadherin expression was down-regulated in gastric cancer cells with protocadherin 7 depletion. Our data indicated that protocadherin 7 may play important roles in the invasion and metastasis of gastric cancer, and protocadherin 7 could suppress cell migration and invasion through E-cadherin inhibition. Protocadherin 7 can serve as a novel biomarker for diagnostic and prognosis in patients with gastric cancer.

Effect of MTHFR C677T Polymorphism on Methylation Status of E-Cadherin in Gastric Cancer

Background: MTHFR gene is one of the main and effective factors in genes methylation. This gene has a common polymorphism in cordon 677, which can affect its activity. Changing activity rate of this gene can affect methylation rate of tumor suppressor genes and cell membrane proteins and other genes in addition to their expression rate. Therefore, it can be considered as one of the effective factors on producing cancer. Methods: In this descriptive-cross sectional study, 34 cancer and non-cancer tissue samples were studied. Initially, DNA was extracted from samples and then E-cadherin and MTHFR c677t polymorphism were amplified by the polymerase chain reaction (PCR). Methylation status of E-cadherin was evaluated by adding methylation restriction enzyme HpaII and polymorphism of MTHFR c677t was assessment by the restriction fragment length polymorphism (RFLP) method. Results: Methylation status of E-cadherin gene numbers of methylated cases in the cancer group were equal to one and unmethylated cases equal to 33 and numbers of unmethylated cases in the non-cancer group was equal to 34 while there were no methylated cases. In assessment of methylation status of E-cadherin and different genotypes of MTHFR in codon number 677 in cancer samples, number of CC, CT and TT genotypes were equal to 0, 1 and 0 in the methylated group and equal to 6, 27 and 1 in the unmethylated group, respectively. Conclusions: According to this observation, another factor such as oncogenes activity may cause cancer in samples but CT genotype of MTHFR can be considered as an effective factor in creating cancer.

Expression of FoxM1 and the EMT-associated protein E-cadherin in gastric cancer and its clinical significance.

The aim of the present study was to investigate the expression of forkhead box M1 (FoxM1) and E-cadherin in tissues of gastric cancer in order to reveal any correlation between FoxM1, E-cadherin and clinicopathological parameters. The association between FoxM1 and E-cadherin in the development and progression of gastric cancer was also investigated. The expression of FoxM1 and E-cadherin in gastric cancer and adjacent normal tissue on tissue microarray was detected using immunohistochemistry. The clinicopathological significance of FoxM1 and E-cadherin in gastric cancer was explored, and the association between FoxM1 and E-cadherin was further examined using statistical techniques. In gastric cancer tissues, the expression of FoxM1 and E-cadherin was strongly positive, but it was weak in normal gastric mucosa. Overexpression of FoxM1 was evident in gastric cancer, and was associated with poor tumor differentiation (P<0.05), advanced tumor state (P<0.05) and lymph node (or distant) metastasis (P<0.05), whereas E-cadherin had the opposite effects. Furthermore, the correlation between FoxM1 and E-cadherin expression in gastric cancer tissue was negative. In conclusion, the high FoxM1 expression and low E-cadherin expression in gastric cancer tissue suggests that these proteins play a critical role in the development and progression of gastric cancer.

Vascular endothelial factor C and E-cadherin relationship with the invasion and metastasis of human gastric cancer

Objective To investigate the expression of vascular endothelial factor C(VEGF-C) and E-cadherin in gastric cancer and explore the relationship between expression of VEGF-C and E-cadherin and the pathogenesis of gastric cancer. Methods Real-time quantitative reverse ranscriptase-polymerase chain rection was applied on 40 cases of gastric cancer and corresponding adjacent noncancerous tissues, in order to detect mRNA expression of VEGF-C and E-cadherin gene.VEGF-C and E-cadherin protein expression in gastric cancer and adjacent normal gastric mucosa were detected by immunohistochemistry.Statistical analysis was carried out to analyze the correlation among VEGF-C, E-cadherin and protein expression with various clinical parameters in these gastric cancer patients. Results The expression of VEGF-C protein in 40 cases of gastric cancer's cancer tissues was 0.461±0.012, significantly higher than that in the adjacent normal tissues(0.036+ 0.023; t=1.101, P<0.05), but E-cadherin expression was significantly lower than that of the adjacent normal tissues(0.079±0.002 vs. 0.321±0.005; t=1.844, P<0.05). There was correlation between VEGF-C mRNA expression with histological grading, TNM staging, lymph node and distant metastasis (t=-1.621, -1.474, -2.378, -1.966, P<0.05). There was correlation between E-cadherin mRNA expression with tumor size, histological grading, TNM stage, there was a significant difference(t=1.875, 1.673, 1.544, P<0.05). VEGF-C and E-cadherin protein expression was negatively correlated(r=-0.688, P<0.05). Conclusion Up-regulated of VEGF-C gene and decreased expression of E-cadherin may play an important role in the carcinogenesis of gastric cancer Key words: Gastric cancer; Vascular endothelial factor C; E-cadherin

Decreased Expression of Caveolin-1 and E-Cadherin Correlates with the Clinicopathologic Features of Gastric Cancer and the EMT Process.

Recent researches and relevant patents have been reported to prove the significant value of Caveolin-1 (Cav-1) in cancer diagnosis and treatment. Our study aimed to study the role of Cav-1 in gastric cancer progression and investigate the relationship between Cav-1/E-cadherin expression and the clinical status of gastric cancer. Immunohistochemistry was applied to detect the expression of Cav-1 and E-cadherin in gastric cancer in a tissue microarray. Real-time PCR was used to further detect the mRNA expression of Cav-1 and E-cadherin in tumor-derived and peritumoral tissues and in different gastric cancer cell lines. The expression of E-cadherin was analyzed by Western Blot and the cell migration ability was examined by Transwell migration assays after downregulation of Cav-1 using siRNA. The staining of Cav-1 and E-cadherin were both strong in all 5 of the normal gastric tissues, while in gastric cancer tissues the staining of Cav-1 and E-cadherin were downregulated (44&33 negative, 21&22weak and 5&15 strong). And their level was correlated with tumor clinical stage, pathological grade, and metastasis status. Moreover, there was a positive correlation between Cav-1 expression and E-cadherin expression in gastric cancer tissues(r = 0.42, P < 0.05). Knockdown of Cav-1 resulted in decreased expression of E-cadherin, cell morphology changes and elevated migration ability of gastric cancer cells. Decreased expression of Cav-1 and E-cadherin may play an important role in the progression of gastric cancer; Knockdown of Cav-1 may promote EMT of gastric cancer by targeting E-cadherin.

Analysis of a cytoskeleton-associated kinase PEAK1 and E-cadherin in gastric cancer

The expression of pseudopodium-enriched atypical kinase 1(PEAK1) has been studied in human cancers. However, their roles in gastric cancer are still unknown. In this study, gastric cancer tissue microarrays were constructed with 159 gastric cancer tissue samples, 150 non-neoplastic gastric epithelium specimens and 152 lymph node samples. Immunohistochemical staining for PEAK1 and E-cadherin was performed. Our study found negative expression of PEAK1 in 113 of 159 (71.1%) gastric cancers, in 46 of 150 (30.7%) non-neoplastic gastric epithelium tissues and in 69 of 94 (73.4%) metastatic lymph nodes. Negative expression of PEAK1 and E-cadherin associated with tumor grading, depth of invasion, lymph node metastases, pTNM stage and macroscopic type. Patients with either positive PEAK1 or E-cadherin expression had a significantly higher survival than those with negative expression. When combined, PEAK1−/E-cadherin− had a significantly poor prognosis than the rest of the patients. The expression of PEAK1 protein was positively correlated with E-cadherin in cancer tissues. Cox regression analyses showed that PEAK1, E-cadherin and PEAK1−/E-cadherin− were independent predictors of overall survival. In conclusion, our findings suggest that loss of PEAK1 may play an important role in carcinogenesis and development of gastric cancer through activating epithelial to mesenchymal transition.

Interaction between cyclooxygenase-2, Snail, and E-cadherin in gastric cancer cells

To investigate the mechanisms of how cyclooxygenase-2 (COX-2) regulates E-cadherin in gastric cancer cells. COX-2 expression in human gastric cancer cell lines SGC-7901, BGC-823, MGC-803 and AGS were measured at the mRNA and protein level. COX-2 rich cell line SGC-7901 was chosen for subsequent experiments. siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB), Snail, and E-cadherin in gastric cancer cells. Gene expression was determined by Western blot and real-time polymerase chain reaction. To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2 (PGE2) on E-cadherin, gastric cancer cells were treated with celecoxib or PGE2, in the presence of NF-κB specific siRNA. Highest expression level of COX-2 was found in SGC-7901 cells, both at mRNA and protein levels. siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail, but an increased expression of E-cadherin in SGC-7901 cells. siRNA mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 cells. However, COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 cells. Treatment of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of E-cadherin. In contrast, treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased E-cadherin. However, siRNA-mediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 cells. COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.

Possible regulatory role of Snail in NF-κB-mediated changes in E-cadherin in gastric cancer

In the present study, we aimed to investigate the involvement of Snail in NF-κB-mediated changes of E-cadherin in gastric cancer. A total of 189 human gastric cancer tissues, and 32 normal gastric mucosal tissues were used to determine the expression levels of NF-κB, E-cadherin and Snail by immunohistochemistry. The correlation between the expression levels and patient clinicopathological data was analyzed. Human gastric cancer cell line SGC7901 was treated with the NF-κB inhibitor PDTC, and the expression levels of E-cadherin and Snail were investigated by qPCR and western blot. NF-κB, E-cadherin and Snail were all detected in normal gastric mucosa and cancer tissues of various differentiation statuses. However, the expression patterns of each protein were different. Strong expression of E-cadherin was detected in normal gastric mucosa, whereas its expression gradually declined in gastric cancer tissues, with weak expression observed in poorly differentiated gastric cancer tissues. In contrast, weak NF-κB and Snail expressions were present in normal gastric mucosa, while their expression levels gradually increased in gastric cancer tissues, with the strongest expression detected in poorly differentiated gastric cancers. The expression of E-cadherin was inversely correlated with that of Snail and NF-κB in the tissues tested. Blockade of NF-κB using its inhibitor PDTC led to a time-dependent reduction in Snail but a time-dependent increase in E-cadherin in SGC7901 cells. These results suggest that in human gastric cancer, loss of E-cadherin may be mediated through NF-κB-induced Snail upregulation. Further studies may reveal whether targeting the NF-κB-Snail-E-cadherin axis could be a useful approach for combating gastric cancer.

Prostaglandin E(2) and interleukin-1β reduce E-cadherin expression by enhancing snail expression in gastric cancer cells.

Inflammation is closely related to the progression of cancer as well as tumorigenesis. Here, we investigated the effect of prostaglandin E2 (PGE2) and interleukin-1β (IL-1β) on E-cadherin expression in SNU719 gastric cancer cells. E-cadherin expression decreased as the dose or exposure time of PGE2 and IL-1β increased, whereas Snail expression increased with dose or time of PGE2 and IL-1β. E-cadherin expression reduced by PGE2 treatment increased after the transfection of Snail siRNA. Neutralization of IL-1β using anti-IL-1β antibody blocked the expression pattern of E-cadherin and Snail occurred by IL-1β treatment. However, there was no synergic effect of IL-1β and PGE2 on the expression pattern of E-cadherin and Snail. In conclusion, inflammatory mediators reduced E-cadherin expression by enhancing Snail expression in gastric cancer cells. Inflammation-induced transcriptional regulation of E-cadherin in gastric cancer has implications for targeted chemoprevention and therapy.

Expression and significance of Cx43 and E-cadherin in gastric cancer and metastatic lymph nodes

Connexin 43(Cx43) and E-cadherin are concurrently expressed in many tumors and were ever classified as tumor suppressors in primary tumors (PT), whereas recent studies showed that these two proteins played specific roles in tumor metastasis. The aim of our study is to determine the expression of Cx43 and E-cadherin in primary gastric tumors (PTs) and matched metastatic lymph nodes (MLNs) and to explore the clinical and pathological implications of expression of these proteins. Immunohistochemical assay was conducted to detect the expression of Cx43 and E-cadherin in PTs and MLNs, and the clinical and pathological implications were analyzed by statistical methods. In PTs, the expression of Cx43 and E-cadherin was significantly reduced, compared to adjacent normal tissues (P < 0.01). The expression of Cx43 and E-cadherin was significantly increased in MLNs compared with PTs (P < 0.01 and P < 0.01, for Cx43 and E-cadherin, respectively), and some Cx43 and E-cadherin-negative PTs developed Cx43 and E-cadherin-positive MLNs. Furthermore, reduced expression of both Cx43 and E-cadherin significantly correlated with poor differentiation, advanced TNM stage, and lymph note metastasis of gastric cancers. Cx43 and E-cadherin expression significantly correlated with each other. We concluded that concurrent reduction in Cx43 and E-cadherin may contribute to the occurrence of gastric cancer. However, concurrent increased expression of Cx43 and E-cadherin may contribute to the efficient metastasis of gastric cancer to the lymph nodes.

Cyclooxygenase-2 Mediated Regulation of E-Cadherin Occurs in Conventional But Not Early-Onset Gastric Cancer Cell Lines

Background: COX-2 and E-cadherin, involved in invasion and metastasis, are molecules critical for gastric carcinogenesis. A relationship between them is documented in non-small cell lung and prostate cancer. We present novel evidence of a relationship between COX-2 and E-cadherin expression in gastric cancer.Methods: Using qPCR and Western blots analysis on celecoxib and PGE2 treated and untreated gastric cancer cell lines derived from tumours of the intestinal type (MKN45, MKN28, AGS3, MKN7) and immunohistochemistry of 178 gastric cancers on tissue microarrays (TMA), we examined the COX-2/E-cadherin relationship.Results: Down-regulation of COX-2 by celecoxib led to up-regulation of E-cadherin mRNA and protein levels in conventional gastric cancer cell lines, whereas expression was down regulated in the early-onset gastric cancer (EOGC) cell line. Immunohistochemistry on TMAs of 178 gastric cancers showed no correlation between COX-2 and E-cadherin expression in the conventional or early gastric cancer groups.Conclusions: The results suggest that COX-2 has an impact on transcriptional regulation of E-cadherin in gastric cancer and our findings further highlight the intriguing nature of EOGCs which appear to have a molecular phenotype distinct from conventional gastric cancer. In addition, our findings also suggest that reduction of COX-2 using nonsteroidal anti-inflammatory drugs in gastric cancer chemoprevention may only be relevant for older patients.

Cyclooxygenase-2 mediated regulation of E-cadherin occurs in conventional but not early-onset gastric cancer cell lines.

Background: COX-2 and E-cadherin, involved in invasion and metastasis, are molecules critical for gastric carcinogenesis. A relationship between them is documented in non-small cell lung and prostate cancer. We present novel evidence of a relationship between COX-2 and E-cadherin expression in gastric cancer. Methods: Using qPCR and Western blots analysis on celecoxib and PGE2 treated and untreated gastric cancer cell lines derived from tumours of the intestinal type (MKN45, MKN28, AGS3, MKN7) and immunohistochemistry of 178 gastric cancers on tissue microarrays (TMA), we examined the COX-2/E-cadherin relationship. Results: Down-regulation of COX-2 by celecoxib led to up-regulation of E-cadherin mRNA and protein levels in conventional gastric cancer cell lines, whereas expression was down regulated in the early-onset gastric cancer (EOGC) cell line. Immunohistochemistry on TMAs of 178 gastric cancers showed no correlation between COX-2 and E-cadherin expression in the conventional or early gastric cancer groups. Conclusions: The results suggest that COX-2 has an impact on transcriptional regulation of E-cadherin in gastric cancer and our findings further highlight the intriguing nature of EOGCs which appear to have a molecular phenotype distinct from conventional gastric cancer. In addition, our findings also suggest that reduction of COX-2 using nonsteroidal anti-inflammatory drugs in gastric cancer chemoprevention may only be relevant for older patients.

Expression of EphA2 and E-cadherin in Gastric Cancer: Correlated with Tumor Progression and Lymphogenous Metastasis

In this study, gastric cancer progression was correlated with the over-expression of erythropoietin-producing hepatocellular (Eph)A2 receptor and down-expression of epithelial cadherin (E-cadherin). Immunohistochemistry of EphA2 and E-cadherin were performed on these tumor samples from 165 primary lesions of gastric cancer. The results showed that expression of EphA2 was obviously increased in gastric cancer tissues (P < 0.01), which was positively correlated with the depth of cancer invasion, tumor-node-metastasis (TNM) stage and lymph node metastasis (P < 0.05). Meanwhile, the expression of E-cadherin was significantly reduced (P < 0.01), which was negatively correlated with the depth of cancer invasion, grade of tumor differentiation, TNM stage and lymph node metastasis (P < 0.05). The correlation between EphA2 and E-cadherin expression was negative (r = -0.198, P = 0.011). In conclusion, either the over-expression of EphA2 or the down-expression of E-cadherin is correlated with cancer progression and lymphogenous metastasis in gastric cancer, suggesting that both of them may play an important role in tumor progression and metastasis.

Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer

Rho GTPases are a family of major regulators of E-cadherin-mediated cell adhesion that are implicated in the carcinogenic process by deregulated expression of the family members itself or of upstream modulators or downstream effectors. Combined investigation of the Rho GTPase Rac1, the effector protein IQGAP1 and the activator Tiam1 in relation to expression or mutation of E-cadherin in gastric adenocarcinomas has not been reported. The aim of the study was to determine the expression and prognostic significance of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric adenocarcinomas. Gastric carcinomas of 76 patients were investigated immunohistochemically in a tissue microarray study for expression of Rac1, IQGAP1, Tiam1 and E-cadherin. Correlations with clinical and follow-up data were examined. Moderate or strong reactivity for Rac1 was observed in 46% and for Tiam1 in 56% of tumors. Expression of IQGAP1 was present in 59% and of E-cadherin in 87% of tumors. While Rac1 and E-cadherin expression were not related to prognosis, a trend was observed between a lack of IQGAP1 expression (log-rank 0.088) as well as presence of Tiam1 (log-rank 0.097) and favorable prognosis in Kaplan–Meier survival analysis. Expression of Rac1 was positively linked to IQGAP1 expression (P=0.007, r=0.343) and tended to be inversely associated with expression of E-cadherin (P=0.055, r=−0.245). In conclusion, we observed deregulated expression of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric cancer. We present evidence that either upregulation (for Rac1 and IQGAP1) or downregulation (for Tiam1 and E-cadherin) occurs. Rac1 and E-cadherin expression were not related to prognosis, while trends pointing to favorable prognosis of patients with Tiam1 expression and a lack of IQGAP1 expression were observed. These results indicate that the investigated regulators of E-cadherin-mediated cell adhesion play a role in gastric carcinogenesis.

Tumor specificity and in vivo targeting of an antibody against exon 9 deleted E-cadherin in gastric cancer

The aim of this study was to evaluate the possibility of using a monoclonal antibody against exon 9 deleted E-cadherin (E-cad delta 9-1) for immunotherapy of gastric cancer. Among nine human diffuse-type gastric cancer cell lines, we selected a cell line expressing exon 9 deleted E-cadherin (HSC-45M2) by direct sequencing. Tumor specificity and tumor specific in vivo targeting of E-cad delta 9-1 were evaluated in nude mouse bearing a tumor derived from HSC-45M2 cell line by immunohistochemical staining. The expression rate of E-cad delta 9-1 was evaluated in 299 gastric cancer patients, and in positive cases, the mutational status of E-cadherin exon 9 was examined. Immunohistochemical staining of various tissues from nude mice showed that only tumor tissue reacted with E-cad delta 9-1. However, immunohistochemical staining of the same tissues after systemic injection of E-cad delta 9-1 showed that reticuloendothelial and hypervascular organs reacted with E-cad delta 9-1, but tumor tissue showed only a slight reaction. Evaluation of the reactivity of 299 gastric cancer patients to E-cad delta 9-1 showed that 4.8% (9/187) of patients, who all had diffuse- or mixed-type gastric cancers, reacted positively, but none of the 112 intestinal-type gastric cancer patients reacted positively. Two of 9 patients (22%) with positive staining to E-cad delta 9-1 were confirmed to have mutant forms of E-cadherin exon 9. Considering that E-cad delta 9-1 showed good tumor specificity and that some diffuse-type gastric cancers were immunopositive to it, this antibody could be a candidate therapeutic antibody against gastric cancers that express mutant E-cadherin.

E-cadherin in gastric cancer

Cadherin is an adhesion molecule and a superfamily of calcium-mediated membrane glycoproteins. E-cadherin is the prototype of the class E-cadherin that links to catenins to form the cytoskeleton. Recent evidence has shown that E-cadherin not only acts as an adhesive, but also plays important roles in growth development and carcinogenesis. It has been recently viewed as an invasion as well as a growth suppressor gene. This review summarizes the recent discoveries on E-cadherin and its role in gastric cancer. In particular, our work on E-cadherin in gastric cancer, including its relation with Helicobacter pylori and clinical applications, are described in detail.