SIRT3 expression as a biomarker for better prognosis in gastric cancer.

BACKGROUND: SIRT3-mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-3-plays an important role in regulating cell metabolism and carcinogenesis. The role of SIRT3 in gastric cancer has not yet been investigated. METHODS: A total of 221 gastric cancer patients who underwent curative surgery were enrolled at the Department of Surgery, Taipei Veterans General Hospital. SIRT3 expression in gastric tissues and tumors were examined in these patients using immunohistochemical staining. Clinicopathologic characteristics and survival were analyzed and compared in gastric cancer patients with or without SIRT3 expression. RESULTS: The 5-year survival rates of patients with or without SIRT3 expression were 51.2 and 39.1 %, respectively (p = 0.005). The 5-year disease-free survival rates of patients with or without SIRT3 expression were 49.6 and 38.0 %, respectively (p = 0.010). Microscopic features showed that there are more poor cell differentiation (p = 0.001), more diffuse-type Lauren's histology (p = 0.018), and more scirrhous-type stromal reactions (p = 0.027) in gastric cancer without SIRT expression. Multivariate analysis with overall survival as an endpoint showed that age (p < 0.001), Lauren's histology (p = 0.007), stromal reaction (p = 0.035), TNM pathologic N category (p < 0.001), and SIRT3 expression (p < 0.001) were significantly correlated with gastric cancer. CONCLUSIONS: Gastric cancer patients with SIRT3 expression have a better prognosis than those without. SIRT3 expression is an independent prognostic marker for overall survival and may act as a tumor suppressor in gastric cancer.

Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced ß5-integrin expression in human gastric cancer SC-M1 cells.

BACKGROUND: Mitochondrial dysfunction has been shown to promote cancer cell migration. However, molecular mechanism by which mitochondrial dysfunction enhances gastric cancer (GC) cell migration remains unclear. METHODS: Mitochondria specific inhibitors, oligomycin and antimycin A, were used to induce mitochondrial dysfunction and to enhance cell migration of human gastric cancer SC-M1 cells. Antioxidant N-acetylcysteine (NAC) was used for evaluating the effect of reactive oxygen species (ROS). Protein expressions of epithelial-to-mesenchymal transition (EMT) markers and the cell-extracellular matrix (ECM) adhesion molecules, the integrin family, were analyzed. A migratory subpopulation of SC-M1 cells (SC-M1-3rd) was selected using a transwell assay for examining the association of mitochondrial bioenergetic function, intracellular ROS content and ß5-integrin expression. Clinicopathologic characteristics of ß5-integrin expression were analyzed in GC specimens by immunohistochemical staining. RESULTS: Treatments with mitochondrial inhibitors elevated mitochondria-generated ROS and cell migration of SC-M1 cells. The protein expression of ß5-integrin and cell surface expression of αvß5-integrin were upregulated, and which were suppressed by NAC. Pretreatments with NAC and anti-αvß5-integrin neutralizing antibody respectively prevented the mitochondrial dysfunction-induced cell migration. The selected migratory SC-M1-3rd cells showed impaired mitochondrial function, higher mitochondria-generated ROS, and increased ß5-integrin expression. The migration ability was also repressed by anti-αvß5-integrin neutralizing antibody. In clinical specimens, GCs with higher ß5-integrin protein expression had more aggressive behavior. In conclusion, mitochondrial dysfunction may lead to GC progression by enhancing migration through mitochondria-generated ROS mediated ß5-integrin expression. GENERAL SIGNIFICANCE: These results support the role of mitochondrial dysfunction in GC progression.

Advanced gastric cancer patients with lymphoid stroma have better survival than those without.

BACKGROUND: Lymphoid stroma is a specific pathologic appearance in gastric cancer. This study aims to compare the clinicopathological characteristics of gastric cancer patients with and without lymphoid stroma. METHODS: From January 1988 to February 2009, 222 out of 1,959 patients with lymphoid stroma of gastric cancer received gastrectomy at the Department of Surgery, Taipei Veterans General Hospital. Clinicopathological characteristics and survival rates were analyzed and compared among the gastric cancer patients with and without lymphoid stroma. For patients with lymphoid stroma, CD20 expression of B lymphocytes and CD3 expression of T lymphocytes were examined using immunohistochemical stains. RESULTS: Advanced gastric cancer patients with lymphoid stroma had better 5-year survival status than those without lymphoid stroma (44.5% vs. 20.5%, P < 0.001). Univariate and multivariate analyses showed that male gender (P = 0.034), tumor invasion depth (P = 0.001), pathological staging (P = 0.006), and Ming's histological classification (P = 0.041) were significantly correlated with patients with lymphoid stroma. B lymphocytes appeared more in Borrmann type III and IV, diffuse Lauren's histological type, and lymph nodes metastases. CONCLUSION: Advanced gastric cancer patients with lymphoid stroma had better prognosis than those without lymphoid stroma. B lymphocytes appeared more in aggressive gastric cancer tissues with lymphoid stroma.

Protein tyrosine-phosphatase expression profiling in gastric cancer tissues.

Protein phosphorylation is an important regulatory mechanism involved in signal transduction and cancers. In comparison to the extensive tyrosine-kinase oncogenesis research, there are only relatively few studies of protein tyrosine-phosphatase expression in cancers. The expression profile for tyrosine-phosphatases was investigated in gastric cancers using RT-PCR and molecular cloning. The present study showed a general PTP expression profile in gastric cancer tissues, with the identification of 22 distinct tyrosine-phosphatases. Following the examination of five PTPs (PTPRA, PTPRB, PTPRD, PTPRG and PTPRZ) using immunohistochemistry, strong association was observed between PTPRA/PTPRZ expression and gastric cancer progression including lymphovascular invasion and liver/peritoneal dissemination.

Effects of COX-2 inhibitor on growth of human gastric cancer cells and its relation to hepatocyte growth factor.

It is known that hepatocyte growth factor binding to its receptor regulates gastric cancer progression and metastasis. HGF was found to up-regulate the expression of cyclooxygenase-2 gene and increases prostaglandin (PG) synthesis in gastric mucosa cells. Overexpression of COX-2 and increased PG secretion have also been found to be involved in the regulation of growth and metastasis of gastric cancer. Results from this study showed that c-Met and COX-2 are expressed in 28 cases (93.3%) and 16 cases (53.3%) of 30 human gastric cancer tissues, respectively. Expressions of c-Met positively correlated with that of COX-2 (r=0.41; P=0.024). Using in vivo and in vitro models to further examine the interaction between c-MET and COX-2, we found that HGF stimulated the growth of SC-M1 cells in a dose-dependent manner. COX-2-specific inhibitor-NS398 inhibited the growth of human gastric cancer SC-M1 cells as well as HGF stimulated the growth of SC-M1 cells in a dose-dependent manner. HGF treatment of SC-M1 cells increased the secretion of PGE2 and this stimulation was blocked by NS398. In vivo SC-M1 tumor model showed that HGF stimulated the tumor growth and NS398 retarded the tumor growth. These results suggest that COX-2-specific inhibitors may play some role on the therapy of gastric cancer patients with high serum HGF level and overexpression of c-Met in tumor.

PTPN3 and PTPN4 tyrosine phosphatase expression in human gastric adenocarcinoma.

BACKGROUND: Degenerated PCR primers, designed according to the consensus tyrosine phosphatase catalytic motifs, were used in order to amplify expressed protein-tyrosine phosphatase molecules from human gastric cancer-derived cells. From such profiles, more than twenty different types of tyrosine phosphatase were identified from gastric cancer tissue. A non-receptor tyrosine phosphatase, PTPN4, was found to be expressed in a tumor-tissue profile with only low frequency. The most closely-related gene to tyrosine phosphatase, PTPN3, has been shown to be mutated in cases of human colorectal cancer, but its expression is cases of gastric cancer is not known. MATERIALS AND METHODS: The mRNA expression of PTPN3 and PTPN4 by RT-PCR was investigated, and the protein expression status of PTPN3 was examined, using immunohistochemistry, to elucidate clinicopathological associations of the PTPN3 and PTPN4 family within human stomach cancer. RESULTS: PTPN3 and PTPN4 were expressed in all gastric cancer cell lines and clinical cancer tissue specimens examined. Following the examination of 92 gastric cancer patients' pathological specimens, PTPN3 expression showed no statistical significance with respect to the patients' survival. A statistically significant correlation between PTPN3 staining and the differentiation status of gastric cancer tissue was, however, observed. CONCLUSION: This finding indicates that both PTPN3 and PTPN4 are expressed within human gastric cancer cells and that PTPN3 seems to play an important role in gastric cancer differentiation and the progression of malignancy.