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Background: Immune checkpoint molecules have critical roles in directing immune responses into co-inhibitory and co-stimulatory signals. Herpes virus entry mediator (HVEM) is a receptor of tumor necrosis factor receptor superfamily with unique features due to its interaction with both inhibitory and stimulatory ligands. The aim of this study was to measure the serum level of the soluble form of HVEM in patients with gastric, colorectal and breast cancers and evaluating its diagnostic and prognostic value. Methods: The concentration of the soluble HVEM (sHVEM) was determined in the serum of 36 patients with breast cancer, 50 patients with colorectal cancer and 59 patients with gastric cancer using ELISA method. Moreover, 50 healthy donors (HD) as well as 31 patients with non-ulcer dyspepsia (NUD) were used as control groups. The patients’ samples were obtained from the Biobank of Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran. Results: The level of sHVEM was significantly higher in patients with gastric (P=0.001) and breast cancer (P=0.01) than in control groups (HD). The higher level of sHVEM was observed in colorectal cancer patients in comparison with HD group, although it was not significant. Moreover, the elevated level of sHVEM was shown to be higher significantly in stage III and IV compared to stage I and II in breast cancer (P=0.03). Similar finding was detected in gastric and colorectal cancers, but not to be statistically significant. Conclusion: The results of the present study suggest that the serum level of sHVEM may be considered as a promising indicator for diagnosis as well as evaluating the progression of cancers such as gastric, breast and colorectal cancers. [ABSTRACT FROM AUTHOR]

Objective(s): Frizzled-7, the most common receptor of the Wnt signaling pathway, was significantly over-expressed in gastric (GC) and colorectal (CRC) cancers and stimulated tumorigenesis. The extracellular domain of Fzd7 (sFzd7) as a decoy receptor, could competitively bound with ligands and antagonize the interaction between Fzd7 receptors and Wnt ligands. Materials and Methods: We expressed and purified the extracellular region of Fzd7 including cysteine-rich domain (33 aa-185 aa) from Escherichia coli by chromatography. The effect of sFzd7 was evaluated on AGS gastric and SW480 colon cancer cell lines expressing high levels of Fzd7 receptor. Accordingly, cell viability and apoptosis were measured using MTT and flow cytometry assays, respectively. Real-Time PCR determined the relative expression of the ß-catenin and cyclin-D1 genes. Results: After three days of treatment with sFzd7, the viability of AGS and SW480 cell lines was decreased in a dose-dependent manner. In addition, sFzd7 at concentrations of 10 and 20 ug/ml increased the rate of apoptosis. Especially at the concentration of 20 ug/ml, the apoptosis rate was remarkably high in AGS (P-value= 0.003) and SW480 cells (P-value= 0.0007). Finally, the expressions of ß-catenin (P-value= 0.01) and cyclin-D1 (P-value= 0.02) were obviously decreased in SW480 cells. The same results were obtained in AGS cells, although not statistically significant. Conclusion: sFzd7 decoy receptor inhibits tumor cell progression by attenuating the Wnt pathway through inhibiting Fzd7 receptors and Wnt ligand interaction. Hence, sFzd7 can be proposed as a candidate therapy for GC and CRC cells with high levels of Fzd7 expression. [ABSTRACT FROM AUTHOR]

To clarify the effect of γδ T cells and invariant Natural Killer T (iNKT) cells in pathophysiology of dyspeptic disorders, number of these two cells in patients with non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), and gastric cancer (GC) were compared.Patients with dyspepsia were divided into three groups of NUD, PUD, and GC according to their endoscopic and histopathological examinations. Helicobacter pylori infection was diagnosed by rapid urease test and histopathology. The number of peripheral blood CD3+TCRγδ(+) T cells and CD3+Va24Ja18+ iNKT cells were determined by flow cytometry. Immunohistochemistry (IHC) was also used for identifying the TCRγδ+ cells.Forty two patients with NUD (31.6%), 44 with PUD (33.1%), and 47 with GC (35.3%) were included in the study. The frequency of CD3+TCRγδ(+) T cells in peripheral blood of patients with GC (2.71±0.25) was significantly lower than that in NUD (3.97±0.32, p<0.05) and PUD groups (3.87±0.32, p<0.05). However, there was no significant difference in CD3+TCRγδ(+) T cell percentage between the NUD and PUD groups. The frequency of TCRγδ(+) lymphocytes was significantly lower in tissue samples from patients with GC (4.81±0.53) than in NUD (11.09±1.09, p<0.0001) and PUD groups (11.11±1.01, p<0.0001). Also, we could not find any significant difference in the percentage of mucosal TCRγδ+ cells between the NUD and PUD groups. The results showed no significant difference in iNKT cells percentage among the three groups of patients.The results suggest that decreasing number of γδ T cells may be related to development and progression of gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose: Vascular endothelial growth factor (VEGF) is one of the most important growth factors for metastatic tumors. To clarify the role of VEGF-A and C in patients with peptic ulcer disease (PUD) or gastric cancer (GC), we evaluated the expression levels of these two molecules. We also analyzed the effect of Helicobacter pylori infection on VEGF-A and C expression levels. Materials and Methods: Patients with dyspepsia who needed diagnostic endoscopy were selected and divided into three groups: nonulcer dyspepsia (NUD), PUD, and GC, according to their endoscopic and histopathological results. Fifty-two patients with NUD, 50 with PUD, and 38 with GC were enrolled in this study. H. pylori infection was diagnosed by the rapid urease test. After RNA extraction and synthesis of cDNA, the expression levels of VEGF-A and C were determined by quantitative reverse transcriptase polymerase chain reaction. Results: The VEGF-C expression level in the PUD and GC groups was significantly higher than that in the NUD group. Moreover, the VEGF-A expression level in the PUD and GC groups was higher than in the NUD group, although the differences were not statistically significant. Significant positive correlations were also observed between the expression levels of these two molecules in the PUD and GC groups. In addition, the expression levels of these two molecules were higher in H. pylori positive patients with PUD or GC than in H. pylori negative patients of the same groups; however, these differences did not reach statistical significance. Conclusions: Up-regulation of VEGF-C expression during gastric mucosal inflammation may play a role in the development of peptic ulcers or GC. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim of this study was to compare the proportion of natural killer (NK) and natural killer T (NKT)-like cells in dyspeptic disorders caused by Helicobacter pylori (H. pylori). Materials and methods: In a case-control study, 27 patients with gastric cancer (GC), 25 patients with peptic ulcer (PUD), and 22 patients with non-ulcer dyspepsia (NUD) were enrolled. After endoscopic diagnosis, the proportions of NK cells subsets (CD3-CD56+ and CD3-CD16+), as well as NKT-like cells (CD3+CD56+) in peripheral blood were determined by flow cytometry. The frequency of CD8+ and CD8- NK cell subsets were also determined. H. pylori infection was confirmed in all study subjects using the rapid urease test and histopathology. Results: The frequencies of CD3-CD16+ NK, CD3-CD56+ NK, and CD3+CD56+ NKT-like cells in patients with gastric cancer infected by H. pylori were significantly lower than those in patients with non-ulcer dyspepsia (P < 0.001, P = 0.050, and P = 0.020, respectively). However, these cell populations showed no significant difference between the PUD and NUD groups. Further analysis showed that high numbers of CD8- NK cells in the blood were CD56+ and CD16+ phenotypes. Conclusion: This study showed decreased numbers of NK and NKT-like cell populations in patients with gastric cancer compared to those with non-ulcer dyspepsia. It is thus suggested that these cells may limit the prolonged inflammation by H. pylori, which, in turn, reduce the risk of gastric cancer. [ABSTRACT FROM AUTHOR]

Background and purpose: Gastric cancer has been considered as the second lethal cancer throughout the world and the incidence of this cancer in Iran is 25 in 10000 people per year. Interleukin-11 (IL-11), a member of IL-6 family, may play some role in developing gastric cancer via activation of the JAK/STAT signaling pathway. In this study, the level of IL-11 gene expression was determined in gastric biopsy specimens of patients with and without gastric cancer. Materials and methods: In this case-control study, biopsy specimens were collected from Imam Khomeini Hospital and Tooba Clinic in Sari. Based on the histopathologic and endoscopic assessments, patients were divided into two groups of gastric cancer patients (n=45) and those without gastric cancer (n=45). To determine the level of gene expression of IL-11, SYBR Green Real-time PCR method was employed. The obtained data were analyzed using REST 2008 and SPSS16. Results: The histopathology of the biopsy specimens were determined as intestinal adenocarcinoma (93.4%), diffused adenocarcinoma (4.4%), and carcinoid tumor (2.2%). The level of IL-11 gene expression was significantly higher in gastric cancer samples compared with individuals (p<0.05); moreover, no change in the expression of this gene in patients with other digestive complications without gastric cancer was observed (p=0.81). Conclusion: It is suggested that IL-11 has relationship with developing gastric cancer and it is likely involved in the process of tumorgenesis, proliferation and survival by increasing the anti-apoptotic activity. [ABSTRACT FROM AUTHOR]

The immunopathological mechanism underlying intestinal metaplasia and gastric cancer remain incompletely understood. Regarding the role of B- and T -lymphocyte attenuator (BTLA) / herpesvirus entry mediator (HVEM) in tumorigenesis, this research was conducted to determine the BTLA/HVEM expression in development of gastric cancer. Gastric biopsy and peripheral blood was drawn from 32 non-ulcer dyspepsia (NUD) as control group, 19 intestinal metaplasia (IM), and 63 gastric cancer (GC). BTLA/HVEM expression were analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction. Soluble HVEM (sHVEM) and anti -Helicobacter pylori IgG antibody were assessed by ELISA. Our result showed that BTLA mRNA and protein were significantly increased in advanced stages of gastric cancer. HVEM was higher only at the protein level in the GC group. The sHVEM concentration was also higher in the GC group than in the NUD groups. In addition, we observed H. pylori -positive samples had a lower H-score of HVEM than H. pylori -negative ones. These results suggest that BTLA/HVEM/sHVEM inhibitory pathway is involved in immune regulation and progression of gastric cancer. Therefore, this inhibitory pathway might be a therapeutic target to further immunotherapy of gastric cancer. [ABSTRACT FROM AUTHOR]