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

Alterations of the cell adhesion molecule E-cadherin have been demonstrated in sporadic and hereditary gastric carcinomas. A cell adhesion molecule with functional similarity to E-cadherin is desmoglein 2 (Dsg2), a major component of the desmosomes. In this study, we investigated whether alterations of Dsg2 are involved in gastric carcinogenesis and whether germline mutations contribute to a genetic predisposition in familial gastric cancer patients with no germline mutations in the E-cadherin gene. Seventy-five formalin-fixed, paraffin-embedded tissues from 37 familial and 38 sporadic gastric carcinomas were analysed for Dsg2 expression by immunohistochemistry. DNA from 31 familial gastric cancer patients was analysed for germline mutations and five sporadic tumours were analysed for somatic mutations by DHPLC. Of the 75 tumours, 25 (33%) demonstrated abnormal (reduced and/or non-membrane-associated) Dsg2 expression. There was a trend towards more frequent abnormal expression in diffuse type (42%) than in intestinal type tumours (18%) (p = 0.066). One germline missense variant leading to a non-conservative amino acid change (c. 2810 C > A, Thr 937 Asn) was found in a familial gastric cancer patient with a diffuse type tumour. No somatic mutations were identified. The observed abnormal expression of Dsg2 protein suggests that this molecule is involved in the carcinogenesis of a subset of gastric carcinomas, in particular of the diffuse type. Somatic mutations in the gene do not seem to be a very frequent inactivation event and the finding of no clear pathogenic germline mutation rules out Dsg2 as a major gastric cancer predisposition gene.
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PMID:Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer. 1602 35

Cyclins condition the course of a cell cycle through the activation of appropriate serine-threonine kinases. Any variation in the cyclins' expression result in pathologies of the cell division, including neoplastic proliferation. Activity of the complexes of cyclins D1 and E with appropriate cyclin-dependent kinases may be inhibited by protein P21 (WAF1/CIP1) which functions as a cell growth cycle inhibitor. As yet, there have been rather few reports on the prognostic value of this cyclin expression assessment in gastric cancer, the kind of neoplasm still characterized by very poor prognosis. The study aimed at the assessment of expression levels of cyclins D1 and E in surgically removed gastric cancers, including the analysis of this prognostic value parameter, and attempted to determine some correlations between the expression of the examined cyclins and selected histoclinical and molecular parameters such as: patients' age and gender, histological type according to the Lauren classification, cancer stage (TNM), degree of histological malignancy (G) and level of expression of the cell-cycle regulatory genes protein products--P53, P21, P27. Immunohistochemical analysis was performed on specimens obtained from radical stomach resections of 80 patients treated in the period 1992-1997 for gastric cancer stage I-IIIB (TNM-UICC) at the Department of Surgical Oncology, Medical University of Lodz. For immunohistochemical examinations, the LSAB system was used, designed for assessment of antigen expression. In statistical analysis, Fisher's exact test was applied to evaluate correlations between the analyzed variables and Mantel-Haenschel's test to evaluate their collinearity. For the evaluation of the effect of the analyzed variables on postoperation survival and recurrence-free survival the Cox regression model was used. When analyzing the prognostic value and survival period in association to the cyclins D1 and E expression levels, a statistically significant correlation was found only in relation to cyclin E expression: a survival period of minimum 5 year duration was significantly higher in the group displaying a negative, or only faintly positive, reaction to the presence of cyclin E, than in the group with a strongly positive response. Moreover, the analysis showed statistically significant non-linear dependence between the histological type of cancer in the Lauren classification as well as a degree of histological malignancy and the level of cyclin E expression, and a negative correlation between the level of cyclin E expression and the stage of cancer; In addition, a positive correlation between the level of P53 and cyclin E expression as well as statistically significant non-linear correlation between the level of cyclin E expression and the level of protein P21 expression was observed. However, no statistically significant correlations were found between the level of expression of the two cyclins and the level of protein P27 expression or between the levels of cyclin D1 and E expression in gastric cancer. Out of the two types of evaluated cyclins only cyclin E can be considered a significant regulatory factor and a useful prognostic parameter in gastric cancer.
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PMID:A study on the prognostic value of cyclins D1 and E expression levels in resectable gastric cancer and on some correlations between cyclins expression, histoclinical parameters and selected protein products of cell-cycle regulatory genes. 1627 May 27

The genomic DNA of toll-like receptor (TLR) 2, TLR4, radioprotective 105, TLR6, and TLR9 were examined for mutations in 48 patients with gastric cancer. Of these, 22 had well-differentiated and 20 had poorly-differentiated adenocarcinomas, the latter group including 10 with signet ring cell carcinomas. The remaining 6 had gastric adenomas. Ten healthy volunteers with no family history of malignant diseases served as controls. DNA was extracted from peripheral blood and subjected to electrophoresis using PCR oligonucleotide primers. The resultant gel was analyzed with a DNA sequencer. None of the healthy volunteers, patients with gastric adenomas or those with well-differentiated gastric adenocarcinomas showed mutations. However, 8 of the 20 with poorly-differentiated gastric adenocarcinoma showed heterozygosity at the 135th position of the amino acid sequence of TLR4, and a mutation from threonine to alanine was found at this site. Analysis of the entire available amino acid sequence of TLR4 revealed that this mutation occurred at a leucine-rich repeat corresponding to one of its extracellular components. This suggests a disturbance in the protein phosphorylation reaction of TLR4, and that this disturbance is related to the development of poorly-differentiated gastric adenocarcinomas.
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PMID:Heterozygous Thr 135 Ala polymorphism at leucine-rich repeat (LRR) in genomic DNA of toll-like receptor 4 in patients with poorly-differentiated gastric adenocarcinomas. 1678 56

Polo-like kinase 1 (Plk1) is one of the serine/threonine kinases involved in various mitotic processes, such as centrosome maturation and chromosome segregation. Although Plk1 is increased in several tumor types, the effect of Plk1 in gastric cancer is not clear because of the limited patient numbers in previous studies. This study was performed to investigate the prognostic significance and the expression profiles of Plk1 in gastric carcinoma tissues from 280 Korean patients. The expression of Plk1 was analyzed by reverse transcriptional PCR and a tissue array using immunohistochemical staining method in gastric adenocarcinoma tissues. The oncogenic potential of Plk1 was analyzed by using Plk1-specific small interference RNA in gastric cancer cells. The message of Plk1 was increased in various gastric cancer cell types and in primary cancer specimens in comparison with normal tissue. The expression rate of Plk1 was 95% (268/280) in gastric carcinoma patients. Although Plk1 expression had no specific correlation in male or female patients, among the differentiation types of cancer, its expression was generally increased in gastric cancers. Plk1 expression was significantly associated with accumulation of proliferation-related genes and oncogenes, and reversely correlated with tumor suppressor genes. When Plk1 expression was blocked, cancer cell growth was inhibited and apoptotic phenotypes were detected. Overexpression of Plk1 was important in abnormal proliferation and showed oncogenic potential in gastric cancer. Plk1 might have potential as a tumor prognostic marker for gastric cancer.
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PMID:Oncogenic effect of Polo-like kinase 1 expression in human gastric carcinomas. 1686 74

Protein kinase D2 (PKD2), a member of the PKD family of serine/threonine kinases, is localized in various subcellular compartments including the nucleus where the kinase accumulates upon activation of G-protein-coupled receptors. We define three critical post-translational modifications required for nuclear accumulation of PKD2 in response to activation of the CCK2 receptor (CCK2R): phosphorylation at Ser706 and Ser710 within the activation loop by PKC eta leading to catalytic activity and phosphorylation at Ser244 within the zinc-finger domain, which is crucial for blocking nuclear export of active PKD2 by preventing its interaction with the Crm-1 export machinery. We identify CK1delta and epsilon as upstream activated kinases by CCK2R that phosphorylate PKD2 at Ser244. Moreover, nuclear accumulation of active PKD2 is a prerequisite for efficient phosphorylation of its nuclear substrate, HDAC7. Only nuclear, active PKD2 mediates CCK2R-induced HDAC7 phosphorylation and Nur77 expression. Thus, we define a novel, compartment-specific signal transduction pathway downstream of CCK2R that phosphorylates PKD2 at three specific sites, results in nuclear accumulation of the active kinase and culminates in efficient phosphorylation of nuclear PKD2 substrates in human gastric cancer cells.
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PMID:Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. 1796 9

The signalling pathways leading to the development of Helicobacter pylori-induced gastric cancer remain poorly understood. We tested the hypothesis that H. pylori infections involve the activation of Akt signalling in human gastric epithelial cancer cells. Immunoblot, immunofluorescence and kinase assays show that H. pylori infection of gastric epithelial cells induced phosphorylation of Akt at Ser 473 and Thr 308. Mutations in the H. pylori virulence factor OipA dramatically reduced phosphorylation of Ser 473, while the cag pathogenicity island mutants predominantly inhibited phosphorylation of Thr 308. As the downstream of Akt activation, H. pylori infection inactivated the inactivation of glycogen synthase kinase 3beta at Ser 9 by its phosphorylation. As the upstream of Akt activation, H. pylori infection activated epidermal growth factor receptor (EGFR) at Tyr 992, phosphatidylinositol 3-OH kinase (PI3K) p85 subunit and PI3K-dependent kinase 1 at Ser 241. Pharmacologic inhibitors of PI3K or mitogen-activated protein kinase kinase (MEK), Akt knock-down and EGFR knock-down showed that H. pylori infection induced the activation of EGFR-->PI3K-->PI3K-dependent kinase 1-->Akt-->extracellular signal-regulated kinase signalling pathways, the inactivation of glycogen synthase kinase 3beta and interleukin-8 production. The combined functions of cag pathogenicity island and OipA were necessary and sufficient for full activation of signalling at each level. We propose activation of these pathways as a novel mechanism for H. pylori-mediated carcinogenesis.
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PMID:Helicobacter pylori activate epidermal growth factor receptor- and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3beta phosphorylation. 1878 53

The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G(2) and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer. PF-03814735 is a novel, potent, orally bioavailable, reversible inhibitor of both Aurora1 and Aurora2 kinases that is currently in phase I clinical trials for the treatment of advanced solid tumors. In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 produces significant inhibition of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral administration of PF-03814735 to mice bearing human xenograft tumors produces a reduction in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition. These results support the clinical evaluation of PF-03814735 in cancer patients. Mol Cancer Ther; 9(4); 883-94. (c)2010 AACR.
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PMID:PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. 2035 18

Recently, the succinate dehydrogenase subunit B gene, SDHB, has emerged as a novel tumor suppressor. In this study, we have examined the genetic and epigenetic alterations of the SDHB gene in sporadic gastric adenocarcinomas in order to investigate if the SDHB gene is involved in gastric carcinogenesis. The expression of SDHB proteins was also examined with immunohistochemistry and Western blot in 184 and eight gastric cancers, respectively. There was loss or reduced expression of SDHB in 45 (24.5%) of the 184 gastric cancers. Statistically, altered expression of SDHB was not associated with clinicopathological parameters, including tumor differentiation, location, depth of invasion, and lymph node metastasis (P > 0.05). Western blot analysis showed a reduced expression of SDHB in four (50.0%) of the eight paired gastric cancer tissues. Genetic analysis showed one missense mutation, GCC --> ACC (Ala --> Thr) at codon 29. In addition, promoter hypermethylation was not detected in the gastric cancer samples. This is the first investigation of the genetic and protein expression analysis of the SDHB gene in gastric cancers. Our results suggest that genetic, epigenetic, and protein expression pattern alterations of the SDHB gene might play a minor role in the development or progression of gastric cancers.
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PMID:Analysis of succinate dehydrogenase subunit B gene alterations in gastric cancers. 2061 33

Aurora-A, encoding serine/threonine kinases with a key role in mitosis has been demonstrated to be involved in tumor progression. Hematogenous and lymphatic metastasis are also involved in cancer progression. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) have been implicated in tumor-related angiogenesis and lymphagenesis. The purpose of this study was to analyze the expression and prognostic significance of Aurora-A, VEGFs and VEGFRs in gastric cancer. The expression profiles of Aurora-A, VEGF-A and VEGF-D in gastric cancer cell lines were detected employing real-time reverse transcription polymerase chain reaction and Western blot analysis. The expression levels of Aurora-A, VEGF-A/VEGFR-2, VEGF-D/VEGFR-3 and clinicopathological characteristics were analyzed in 89 gastric cancer patients treated with curative surgery. Univariate analysis demonstrated that histological grade (P=0.052), TNM stage (P<0.001), lymphovascular involvement (P<0.001), Aurora-A (P<0.001) and VEGF-D (P=0.048) were prognostic factors. The presence of Aurora-A was correlated with tumor progression (P=0.053) and shorter survival (P=0.001). Cox multivariate regression analysis demonstrated that Aurora-A positive expression, stage III-IV and lymphovascular involvement were independent unfavorable prognostic factors in gastric cancer. Aurora-A positive expression was predictive for worse outcome in patients without lymph node metastasis (P<0.05) and in patients with stage III-IV (P<0.001). Aurora-A could serve as an independent prognostic marker in gastric cancer and could identify patients with worse outcome even in a relatively early and local disease, thus offering valuable information for administering individualized treatment and/or surveillance for these patients.
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PMID:Aurora-A as an independent molecular prognostic marker in gastric cancer. 2147 65

The hMSH2 gene participates in DNA mismatch repair and its mutation can result in genetic instability of the human genome which is an important feature of tumorigenesis. In this study, genetic alterations of the hMSH2 gene were examined in 43 ovarian, 36 non-small cell lung (NSCL), 31 poorly differentiated gastric, 15 endometrial, and 11 colon cancers, nine gastric cancer cell lines, 41 adult T-cell leukemias (ATLs), two ATL cell lines, and 37 non-Hodgkin's lymphomas (NHLs), using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique. Microsatellite instability (MSI) was also investigated for ovarian, NSCL, and colon cancers. The incidence of MSI was 1/36 (3%) for NSCL, 2/23 (9%) for ovarian, and 1/11 (9%) for colon cancers. Missense base changes of the hMSH2 gene were identified in two gastric cancer patients (ATG to ATA resulting in Met changing to Ile at codon 688 in exon 13 and ACA to GCA resulting in Thr changing to Ala at codon 803 in exon 14). These mutations were found in samples with no MSI. One ovarian and one gastric cancer, and six ATL samples showed two types of polymorphisms of hMSH2 (CTT to TTT resulting in Leu changing to Phe at codon 390 in exon 7 and CAG to AAG resulting in Gin to Arg at codon 419 in exon 7). Our data suggest that MSI and hMSH2 mutations are uncommon in sporadic tumors.
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PMID:Mutational analysis of the hMSH2 gene in a wide variety of tumors. 2152 33


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