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)

Helicobacter pylori, the main cause of chronic gastritis, plays a central role in the etiology of peptic ulcer disease and gastric cancer. In vitro studies have shown that H. pylori increases gastric epithelial cell turnover, thus increasing the risk for the development of neoplastic clones. The mechanisms by which H. pylori promotes perturbation of cell proliferation are not yet elucidated. To investigate whether products released by H. pylori in culture media interfere with cell cycle progression of human gastric epithelial cells, four cell lines (MKN 28, MKN 7, MKN 74, and AGS) were incubated in the presence of H. pylori broth culture filtrate. Cell cycle analysis showed that a H. pylori-released factor(s) significantly inhibited the G1- to S-phase progression of MKN 28 and MKN 7 cell lines, with a reversible, nonlethal mechanism, independent of the expression of VacA, CagA, and/or urease. The cell cycle inhibition occurred concomitantly with an increase in p27(KIP1) protein levels, a reduction in Rb protein phosphorylation on serine residues 807-811, and a significant decrease in cyclin E-associated cdk2 activity. In contrast, the cell cycle progression of MKN 74 and AGS cell lines was not affected by the H. pylori-released factor(s). In normal human fibroblasts, G1-phase cell accumulation was concomitant with the reduction in Rb protein phosphorylation; that, however, appeared to be dependent on p21(WAF1/CIP1) rather than on p27(KIP1) protein. A preliminary characterization showed that the molecular mass of the partially purified cell cycle inhibitory factor(s) was approximately 40 kDa. These results suggest that H. pylori releases a soluble factor(s) that may affect cell cycle progression of gastric epithelial cells through elevated levels of cdk inhibitor p27(KIP1). This factor(s) might act in vivo on noncolonized distant cells, the most proliferating cells of human gastric mucosa.
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PMID:Helicobacter pylori releases a factor(s) inhibiting cell cycle progression of human gastric cell lines by affecting cyclin E/cdk2 kinase activity and Rb protein phosphorylation through enhanced p27(KIP1) protein expression. 1244 Nov 36

Helicobacter pylori, a gram-negative spiral bacterium, has been associated with chronic gastritis and gastric cancer. HP 99, isolated from the Korean patients, and NCTC 11637, obtained from ATCC, have different genotypes. The present study aims to investigate whether these H. pylori strains show the discrepancy for activating transcription factors (NF-kappaB, AP-1, C/EBP) and induction of cyclooxygenase-2 (COX-2) gene in gastric epithelial AGS cells. After treatment of H. pylori to AGS cells at the ratio of 300:1, the activation of transcription factors was assessed by electrophoretic mobility shift assay. COX-2 protein was determined by Western blot analysis. The level of 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), a COX-2 product, was measured in the medium by enzyme-linked immunosorbent assay. As a result, both H. pylori strains similarly induced COX-2 expression via activation of NF-kappaB, not C/EBP, and increased the level of 6-keto-PGF(1alpha). HP 99 showed much higher activation of AP-1 compared to NCTC 11637. NF-kappaB might play an important role in COX-2 expression in H. pylori-induced gastric inflammation as compared to other transcription factors.
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PMID:Cyclooxygenase-2 expression by transcription factors in Helicobacter pylori-infected gastric epithelial cells: comparison between HP 99 and NCTC 11637. 1248 15

Camptothecin, a topoisomerase I inhibitor, is a well-known anticancer drug. However, its mechanism has not been well studied in human gastric cancer cell lines. Camptothecin induced apoptotic cell death in human gastric cancer cell line AGS. Z-VAD-fmk, pan-caspase inhibitor, blocked apoptotic phenotypes induced by camptothecin suggesting that caspases are involved in camptothecin-induced cell death. An inhibitor of caspase-6 or -8 or -9 did not prevent cell death by camptothecin. Various protease inhibitors failed to prevent camptothecin-induced cell death. These results suggest that only few caspases are involved in camptothecin-induced cell death. Camptothecin induced phosphorylation of ERK1/2, JNK, and p38 MAPK, in a dose and time-dependent manner in AGS. Z-VAD-fmk did not affect MAPK signaling induced by camptothecin suggesting that caspase signaling occurs downstream of MAPK signaling. Blocking of p38 MAPK, but not ERK1/2, resulted in partial inhibition of cell death and PARP cleavage by camptothecin in AGS. Taken together, MAPK signaling is associated with apoptotic cell death by camptothecin.
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PMID:MAPK signaling is involved in camptothecin-induced cell death. 1252 Dec 96

The expression of metallothionein (MT)-3 is often markedly reduced in gastric carcinoma (GC). The molecular mechanism of this MT-3 downregulation is unknown. Transcriptional silencing of MT-3 by methylation of CpG island was investigated by nucleotide sequencing and denaturing high performance liquid chromatography (DHPLC) analyses. We found that normal brain tissue and a xenografted GC that expressed MT-3 mRNA had unmethylated regions of the CpG island in intron1 of this gene. On the other hand, gastric cancer cell lines AGS and MKN445, a xenografted GC, and a representative primary gastric cancer that had no expression of MT-3 mRNA demonstrated hypermethylation of the MT-3 intron1 CpG island. Treatment of the gastric cancer cell lines with 5-azacytidine resulted in new expression of MT-3 mRNA in these cells. A quantifying DHPLC assay was developed to determine the methylation status of this specific region of the MT-3 gene. Fifty-eight primary GC and their corresponding normal gastric epithelial tissues, and 34 normal gastric mucosa were analyzed for MT-3 methylation by DHPLC in the region of methylation abnormalities initially identified. Our DHPLC analyses of the methylated MT-3 product demonstrated that the primary gastric cancers have an average methylation percentage of 6.3% per tumor compared with 2.4% in normal gastric tissues (P < 0.05). The MT-3 was not methylated in all of eight P53-positive GCs and hypermethylated in eight of 13 P53-negative cases by immunohistochemistry staining (P = 0.007). In conclusion, the CpG island in the MT-3 intron1 are abnormally hypermethylated in many gastric carcinomas and may account for the downregulation of MT-3 in gastric carcinogenesis.
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PMID:Hypermethylation of metallothionein-3 CpG island in gastric carcinoma. 1253 45

Helicobacter pylori induces activation of mitogen-activated protein kinases (MAPKs). However, its effect on H. pylori-induced apoptosis has not been evaluated. Thus, we examined whether H. pylori-induced extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 MAPK activation affects gastric epithelial cell apoptosis and bcl-2 family gene expression, especially in relation to the cagA status of an H. pylori strain. In flow cytometric and oligonucleosome-bound DNA enzyme-linked immunosorbent assay analyses, infection with cagA(+) H. pylori strains induced gastric cancer cell apoptosis in AGS cells more prominently than infection with cagA mutants. Activation of ERK1/2 and p38 MAPKs was also more prominent in cagA(+) strains. Pretreatment with a MEK inhibitor (PD98059) inhibited ERK1/2 activation and increased H. pylori-induced apoptosis significantly. This increased apoptosis was accompanied by decreased antiapoptotic bcl-2 mRNA expression among bcl-2-related genes (bcl-2, bax, bak, mcl-1, and bcl-X(L/S)), and the effect was also more prominent in the cagA(+) strains. However, the alteration of bcl-2 gene expression was not accompanied by protein level changes. Inhibition of p38 using specific inhibitor SB203580 decreased H. pylori-induced apoptosis but resulted in little alteration of bcl-2-related gene expression. In conclusion, H. pylori-induced ERK1/2 activation, especially by the cagA(+) H. pylori strain, may play a protective role against gastric epithelial cell apoptosis partially through maintenance of bcl-2 gene expression.
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PMID:Effect of inhibition of extracellular signal-regulated kinase 1 and 2 pathway on apoptosis and bcl-2 expression in Helicobacter pylori-infected AGS cells. 1254 May 63

Differentiation-inducing factor-1 (DIF-1) is a chlorinated hexaphenone isolated from Dictyostelium. DIF-1 exhibits antitumor activity in several types of mammalian tumor cells, although the underlying mechanisms remain unknown. On the other hand, recent studies indicate that constitutively activated STAT3 acts as an oncogene and could be a target for antitumor drug. In the present study, we examined the effects of DIF-1 on proliferation of gastric cancer cell lines as well as on its signal transduction pathways, focusing mainly on STAT proteins. DIF-1 inhibited proliferation of gastric cancer cells. Western blot analysis and electrophoretic mobility shift assay showed that DIF-1 inhibited STAT3 activity in an MEK-ERK-dependent manner in gastric cancer cell lines, AGS and MKN28. Moreover, blockade of STAT3 activity by ectopic expression of dominant-negative STAT3 or the Janus kinase inhibitor, tyrphostin AG490, inhibited cell growth of AGS cells. These results suggest that STAT3 activity plays an important role for cell growth in AGS cells, and raises the possibility that inhibition of STAT3 activity is one of the mechanisms responsible for the antitumor effect of DIF-1 in these cells.
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PMID:Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway. 1255 68

Substantial evidence show a higher incidence of gastric cancer in smokers than nonsmokers and that cigarette smoking is highly associated with colon cancer. The present study was designed to examine the effect of cigarette smoke extracts on gastric and colon cancer cell proliferation, which is important for tumor growth. Two different cell lines were used. One was gastric cancer cell line AGS, and the other was colon cancer cell line HT-29. It was found that cigarette smoke extracts stimulated cell proliferation and c-myc expression in AGS cells. Furthermore, this proliferative action was partially blocked by the c-myc antisense. However, the extracts significantly inhibited HT-29 cell proliferation and suppressed c-myc expression. In conclusion, cigarette smoke extracts stimulated AGS cell proliferation, while inhibiting HT-29 proliferation, which were partially mediated by a c-myc-related pathway. The former action may play a contributory role in the carcinogenic action of cigarette smoking in the stomach.
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PMID:Differential effects of cigarette smoke extracts on cell proliferation in gastric and colon cells. 1274 85

Epithelial cell responses to bacterial infection include induction of matrix metalloproteinase 7 (MMP-7). Here, we identify increased MMP-7 expression in the gastric epithelium in response to the oncogenic bacterium Helicobacter pylori, and report on the mechanisms and consequences for gastric epithelial cell migration. In patients infected with H. pylori, there was increased MMP-7 in gastric biopsies detected by western blot. MMP-7 was localized to the advancing edge of migrating gastric epithelial cell colonies, including lamellipodia. Rates of spreading of gastric gland cells were higher in H. pylori-infected cultures compared with control, and this was inhibited by antisense oligonucleotides to MMP-7. Complementary data were obtained in a gastric cancer cell line (AGS cells). In the latter, H. pylori induced expression of an MMP-7-luciferase promoter/reporter vector through mechanisms that involved activation of Rho and Rac. RhoA acted through activation of both NF-kappaB and AP-1, whereas Rac activated NF-kappaB but not AP-1. MMP-7 is commonly upregulated in gastric cancer; since H. pylori is a recognized gastric carcinogen, the data suggest a new mechanism by which the bacterium might predispose towards gastric neoplasia.
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PMID:Stimulation of MMP-7 (matrilysin) by Helicobacter pylori in human gastric epithelial cells: role in epithelial cell migration. 1280 21

H. pylori infection of the gastric mucosa is associated with increased epithelial cell apoptosis. In vitro, interferon-gamma and TNF-alpha have been shown to increase the sensitivity of cells to apoptosis induced by H. pylori. The p53 tumor suppressor gene is frequently mutated in many cancers, including gastric cancer. Since p53 protein can induce apoptosis, we sought to determine whether or not p53 increases the ability of gastric epithelial cells to undergo apoptosis in response to H. pylori-induced cell injury. Human gastric epithelial cell lines, AGS (p53 wild-type) cells and AGS cells infected with HPV E6 gene (AGS-E6) to inactivate p53 were exposed to H. pylori. The p53, p21, and p14ARF proteins were measured in gastric epithelial cells by immunoelectrophoresis. Gastric epithelial cell apoptosis was measured by DNA end-labeling assay (TUNEL) and subG0 cell fractions using flow cytometry, and by agarose gel electrophoresis of DNA. Exposure to H. pylori increased the levels of p53, p21, and p14ARF proteins two fold in AGS cells. Gastric AGS cells with fragmented DNA increased from 1.1% to 68% in after exposure to H. pylori for 24 hr. However, AGS-E6 cells were relatively resistant to apoptosis induced by H. pylori (only 15% of cells underwent apoptosis). In additional experiments, mouse embryonic fibroblasts (MEFs) were used to further investigate the role of ARF in stabilizing p53 after exposure to H. pylori. Wild-type and p19ARF-/- MEFs were exposed to H. pylori and evaluated for activation of p53, p19ARF, and apoptosis. As with AGS cells, H. pylori stimulated a 2-fold increase in p53 and p19ARF in wild-type MEFs; however, there was no increase in p53 in ARF-null MEFs. H. pylori easily stimulated apoptosis in wild-type MEFs, although, the absence of p19ARF significantly reduced the ability of H. pylori to induce apoptosis in these cells. Activation of ARF by H. pylori is important in stabilizing p53 resulting in increased apoptosis. Thus, inactivation of either ARF or p53 in gastric cells may reduce their ability to undergo apoptosis in response to injury induced by H. pylori.
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PMID:p53 and p14 increase sensitivity of gastric cells to H. pylori-induced apoptosis. 1287 Jul 84

Overexpression of urokinase plasminogen activator (uPA) is known to correlate closely with tumor cell invasion and metastasis. In gastric cancer, however, the mechanism for induction of uPA remains to be elucidated. In this study, we investigated the intracellular signaling for uPA expression in human gastric carcinoma cells (AGS, SNU-1, SNU-5, and SNU-638). SNU-638 cells which expressed a high level of uPA was found to be highly invasive on a matrigel, while AGS, SNU-1, and SNU-5 cells with low levels of uPA expression were only slightly invasive. SNU-638 cells showed a much higher P38 MAPK activity than the 3 other cell lines. However, there was no significant difference in the activities of P44/42 MAPK (Erk-1/2), JNK and Akt among the above cell lines. Treatment of SNU-638 cells with SB203580, a specific P38 MAPK inhibitor, reduced both the promoter activity and mRNA expression of uPA. Expression of a vector encoding a mutated-type P38alpha MAPK resulted in decrease in the uPA promoter activity in SNU-638 cells. These results suggest that P38 MAPK signaling pathway is important for uPA expression in gastric SNU-638 cells by enhancing the promoter activity of uPA.
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PMID:P38 MAPK pathway is involved in the urokinase plasminogen activator expression in human gastric SNU-638 cells. 1288 25


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