Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ERBB2 is a member of the epidermal growth factor receptor (EGFR) family. Recent studies revealed that the kinase domain of the ERBB2 gene was mutated in human cancers, including gastric cancer. Despite the importance of cancer metastasis in the pathogenesis of cancers, data on the ERBB2 kinase domain mutation in cancer metastasis are lacking. In this study, to explore the possibility that ERBB2 mutation is involved in the metastasis mechanism, we analyzed the kinase domain of ERBB2 for the detection of somatic mutations in 58 gastric adenocarcinomas with lymph node metastasis. We found one ERBB2 mutation, which was detected in the lymph node metastasis, but not in the primary tumor of the same patient. The ERBB2 mutation was a missense mutation which substituted an amino acid in exon 21 (V832I). We simultaneously analyzed the somatic mutations of EGFR, K-RAS, PIK3CA and BRAF genes in the sample with the ERBB2 mutation, and found that this metastatic carcinoma did not harbor any of the mutations. Our data suggest that ERBB2 kinase domain mutation occasionally occurs in metastatic gastric carcinoma and might play a role in the metastatic process of some gastric carcinomas.
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PMID:ERBB2 kinase domain mutation in a gastric cancer metastasis. 1630 27

A monoclonal antibody to HER2 protein is widely used in the treatment of patients with HER2-overexpressing breast cancer and has also been found to exhibit antitumor activity in human gastric cancer cells that overexpress HER2. The purpose of this study was to evaluate the frequency of HER2 overexpression and concordance between the results for protein expression and gene amplification in both surgical and biopsy specimens of gastric cancer as assessed with two commercial kits, one for immunohistochemistry (IHC) and the other for fluorescence in situ hybridization (FISH). The specimens consisted of formalin-fixed, paraffin-embedded sections of biopsy specimens and surgically resected tumors from 200 cases of invasive gastric cancer that had been treated surgically at the National Cancer Center Hospital East. The lesions were analyzed with the IHC kit, and expression was graded by the United States Food and Drug Administration (FDA)-approved grading system. Gene amplification was evaluated by FISH. IHC revealed HER2 overexpression in 46 of the 200 (23%) cases. The FISH assay was technically successful in 199 cases (99.5%), and gene amplification was observed in 54 cases (27.1%). The concordance rate between the results obtained by IHC and FISH was 86.9%. The concordance rate between the findings in the surgically resected tumors and the 200 pre-treatment biopsy specimens was 88.7%. HER2 expression can be assessed in gastric cancer with a commercial kit as previously reported in breast cancer. Even small biopsy specimens were found to be suitable for evaluating gastric cancer for HER2 overexpression.
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PMID:Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. 1632 35

The keratinocyte growth factor receptor, also known as KGFR/FGFR2 IIIb, is mainly localized in epithelial cells, and participates in the proliferation of these cells. In contrast, a recent study has revealed that the overexpression of KGFR in salivary adenocarcinoma induces growth inhibition, cell differentiation and apoptosis. We attempted to clarify the expression and role of KGFR in normal and cancerous human gastric tissues and cancer cell lines. Reverse-transcription polymerase chain reaction and Western blot analyses showed KGFR mRNA and its protein expression in NUGC-4, KATO-III and MKN-7 gastric cancer cell lines, but not in the NS-8 cell line. Immunohistochemically, KGFR immunoreactivity was weakly detected in the luminal surface of normal gastric epithelial cells. In addition, KGFR immunoreactivity was strongly detected in the nucleus and cytoplasm of many parietal cells. In gastric cancer tissue, KGFR was expressed in the cell membrane and cytoplasm of cancer cells in 46 of 126 (36.5%) cases. KGFR expression in gastric cancer cells was significantly associated with early-type macroscopic findings, shallow invasion of the gastric wall and expansive growth type. KGFR expression tended to correlate with a good prognosis in gastric cancer. These findings indicate that KGFR expression plays important roles in the differentiation of normal gastric epithelial cells and parietal cell functions. Furthermore, a decreased expression level or the non-expression of KGFR in gastric cancer cells may be associated with the proliferation and invasion of gastric cancer cells and a poor prognosis for the patient.
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PMID:Expression of keratinocyte growth factor receptor correlates with expansive growth and early stage of gastric cancer. 1639 83

Vaults are highly conserved, ubiquitous ribonucleoprotein (RNP) particles with an unidentified function. For the three protein species (TEP1, VPARP, and MVP) and a small RNA that comprises vault, expression of the unique 100-kDa major vault protein (MVP) is sufficient to form the basic vault structure. To identify and characterize proteins that interact with the Src homology 2 (SH2) domain of Src and potentially regulate Src activity, we used a pull-down assay using GST-Src-SH2 fusion proteins. We found MVP as a Src-SH2 binding protein in human stomach tissue. Interaction of Src and MVP was also observed in 253J stomach cancer cells. A subcellular localization study using immunofluorescence microscopy shows that epidermal growth factor (EGF) stimulation triggers MVP translocation from the nucleus to the cytosol and perinuclear region where it colocalizes with Src. We found that the interaction between Src and MVP is critically dependent on Src activity and protein (MVP) tyrosyl phosphorylation, which are induced by EGF stimulation. Our results also indicate MVP to be a novel substrate of Src and phosphorylated in an EGF-dependent manner. Interestingly, purified MVP inhibited the in vitro tyrosine kinase activity of Src in a concentration-dependent manner. MVP overexpression downregulates EGF-dependent ERK activation in Src overexpressing cells. To our knowledge, this is the first report of MVP interacting with a protein tyrosine kinase involved in a distinct cell signalling pathway. It appears that MVP is a novel regulator of Src-mediated signalling cascades.
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PMID:Crosstalk between Src and major vault protein in epidermal growth factor-dependent cell signalling. 1644 65

The success of molecular targeted therapy in cancer may depend on the selection of appropriate tumor types whose survival depends on the drug target, so-called "oncogene addiction." Preclinical approaches to defining drug-responsive subsets are needed if initial clinical trials are to be directed at the most susceptible patient population. Here, we show that gastric cancer cells with high-level stable chromosomal amplification of the growth factor receptor MET are extraordinarily susceptible to the selective inhibitor PHA-665752. Although MET activation has primarily been linked with tumor cell migration and invasiveness, the amplified wild-type MET in these cells is constitutively activated, and its continued signaling is required for cell survival. Treatment with PHA-665752 triggers massive apoptosis in 5 of 5 gastric cancer cell lines with MET amplification but in 0 of 12 without increased gene copy numbers (P = 0.00016). MET amplification may thus identify a subset of epithelial cancers that are uniquely sensitive to disruption of this pathway and define a patient group that is appropriate for clinical trials of targeted therapy using MET inhibitors.
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PMID:Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. 1646 7

The anti-tumor effect and mechanism of SEA-Fab' coupled protein on gastric tumor was studied. The target cell Walker-256 was treated with SEA-Fab' synthesized chemically or SEA respectively for 24 h, 36 h or 72 h. PBMC+Walke-256 cells served as controls. The apoptotic index of SEA-Fab' against effector cells was detected. In the mouse gastric cancer models (n = 60), SEA-Fab', SEA and normal saline was injected in experimental group, SEA group and control group respectively. The occurrence and weight of tumor was observed. The results showed that the apoptotic index was significantly higher in the SEA-Fab' (34.6%-68.9%) and SEA group (15.5% -31.9%) than in PBMC+Walker-256 group (5.5%-12.8%) with the difference being significant (P < 0.01). And there was significant difference between SEA-Fab' group and SEA group (P < 0.01). The tumor weight in SEA-Fab', SEA and control groups was 3.64 +/- 0.53 g, 0.78 +/- 0.26 g and 0.49 +/- 0.17 g respectively with the difference being statistically significant between the SEA-Fab' group, SEA group and the control group (P < 0.01). In the SEA-Fab's and SEA groups, there were CD4+ T and CD8+ T cell infiltrates, but in the cotnrol group, no or few T lymphocytes were seen in the mouse tumor tissue. It was concluded that SEA-Fab' was more effective to activate T lymphocytes to kill the tumor cells than SEA used alone. It was feasibility by using the monoclonal antibody as carrier to perform the targeted immunotherapy of gatric tumor.
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PMID:Anti-tumor effect and mechanism of SEA-Fab' coupled protein on gastric tumor. 1646 71

We evaluated the relationship of amplification and polysomy of both the CCND1 and the ERBB2 (alias HER-2/NEU) genes to the overexpression of their proteins in esophageal and gastric cancers and also their association with clinicopathological features. CCND1 gene amplification (45%) was more prevalent than polysomy (25%) in esophageal carcinoma, but the pattern observed was similar in gastric adenocarcinoma (10% amplification, 15% polysomy). For ERBB2, polysomy was a more frequent mechanism than amplification in both esophageal (32.5 vs. 7.5%) and gastric (15 vs. 5%) cancers. Overexpression of cyclin D1 protein was identified in 37.5% of the specimens of esophageal tumors and 35% of gastric tumors, and overexpression of Her-2/neu protein in 12.5 and 7.5%, respectively. The kappa-statistics revealed a fair agreement in both types of tumors only in overexpression and amplification of the CCND1 gene; the ERBB2 gene showed a fair agreement in amplification and polysomy and the level of protein expression in gastric adenocarcinoma. Thus, polysomy 17 could contribute to a high Her-2/neu protein level, at least in gastric cancer. Our data indicated an association with alcohol consumption and the CCND1 gene or protein levels, in both esophageal and gastric cancers.
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PMID:Alterations of the CCND1 and HER-2/neu (ERBB2) proteins in esophageal and gastric cancers. 1649 May 96

The regulatory mechanisms for the proliferation and the particular invasive phenotypes of stomach cancers are not still fully understood. Up-regulations of hepatocytes growth factor (HGF), its receptor (c-Met), and urokinase-type plasminogen activator (uPA) are correlated with the development and metastasis of cancers. In order to investigate roles of HGF/c-Met signaling in tumor progression and metastasis in stomach cancers, we determined effects of a specific MEK1 inhibitor (PD098059) and a p38 kinase inhibitor (SB203580) on HGF-mediated cell proliferation and uPA expression in stomach cancer cell lines (NUGC-3 and MKN-28). HGF treatment induced the phosphorylations of ERK and p38 kinase in time- and dose- dependent manners. Pre-treatment with PD098059 reduced HGF-mediated cell proliferation and uPA secretion. In contrast, SB203580 pre-treatment enhanced cell proliferation and uPA secretion due to induction of ERK phosphorylation. Stable expression of dominant negative-MEK1 in NUGC-3 cells showed a decrease in HGF-mediated uPA secretion. These results suggest that interaction of a MEK/ERK and a p38 kinase might play an important role in proliferation and invasiveness of stomach cancer cells.
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PMID:Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines. 1652 May 50

Gastric adenocarcinoma (GA) is a significant cause of mortality worldwide. The molecular mechanisms of GA remain poorly characterised. Our aim was to characterise the functional activity of the computationally identified genes, NET 1 and MYEOV in GA. Digital Differential Display was used to identify genes altered expression in GA-derived EST libraries. mRNA levels of a subset of genes were quantitated by qPCR in a panel of cell lines and tumour tissue. The effect of pro- and anti-inflammatory stimuli on gene expression was investigated. Cell proliferation and invasion were measured using in an in-vitro GA model following inhibition of expression using siRNA. In all, 23 genes not previously reported in association with GA were identified. Two genes, Net1 and Myeov, were selected for further analysis and increased expression was detected in GA tissue compared to paired normal tissue using quantitative PCR. siRNA-mediated downregulation of Net1 and Myeov resulted in decreased proliferation and invasion of gastric cancer cells in vitro. These functional studies highlight a putative role for NET1 and Myeov in the development and progression of gastric cancer. These genes may provide important targets for intervention in GA, evidenced by their role in promoting invasion and proliferation, key phenotypic hallmarks of cancer cells.
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PMID:Net1 and Myeov: computationally identified mediators of gastric cancer. 1655 34

Cisplatin (CDDP) is a DNA damaging agent and is widely used for treating cancer. While the role of p53 in CDDP-induced cell death has been stressed, evidence exists that CDDP can also kill p53-mutated cells. To investigate the latter mechanism, we performed a comparative study using three different human cell types, SNU-16 (a stomach cancer cell-line), U937 (a leukemic cell-line) and 293T (a kidney fibroblast cell-line), which are defective in terms of p53 activation. A focus was placed on Bcl-2 family proteins, reactive oxygen species (ROS), and mitogen-activated protein kinases. Our results suggest that the ability of CDDP to kill these cells can be mediated by JNK, p38 MAPK and ROS, but not by ERK. It was also found that CDDP can increase the ratio of pro-apoptotic/pro-survival Bcl-2 members. While the importance of these components was found to depend on cell type, JNK was commonly involved in the deaths of all cell types examined. Therefore, the JNK pathway appears to be an ideal target for the modulation of the lethal action of CDDP in multiple types of p53-mutated cells.
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PMID:Cellular components involved in the cell death induced by cisplatin in the absence of p53 activation. 1659 82


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