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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 strains possessing the cag pathogenicity island are associated with the development of gastric cancer. The CagA protein is translocated into epithelial cells and becomes phosphorylated on tyrosine residues within EPIYA motifs, which may be repeated within the variable region of the protein. Strains possessing CagA with greater numbers of these repeats have been more closely associated with gastric carcinogenesis. Phosphorylated CagA leads to epithelial cell elongation, which is dependent on the number of variable-region EPIYA motifs. Thus, determination of the degree of CagA phosphorylation and the number of EPIYA motifs appears to be more important than detection of cagA alone. Determination of the number of EPIYA motifs by nucleotide sequencing, however, is a laborious and expensive process. We describe here a novel and rapid PCR method for determination of the pattern of repeats containing the EPIYA motif. This will aid in the identification of those strains that may be more likely to cause disease.
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PMID:Simple method for determination of the number of Helicobacter pylori CagA variable-region EPIYA tyrosine phosphorylation motifs by PCR. 1569 81

Epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. In the experiments described here using AGS gastric cancer cells, SN38 (the active metabolite of CPT-11) induced tyrosine phosphorylation of EGFR within 5 min, and this was followed by the induction of transcripts and/or proteins of heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-alpha, and interlukin-8 (IL-8). SN38 also activates nuclear factor-kappaB and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib (Iressa, ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.
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PMID:Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. 1572 19

The epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. The findings reported here demonstrate that SN38 (the active metabolite of CPT-11) induces the tyrosine phosphorylation of EGFR within 5 min, followed by the induction of transcripts and/or proteins of the heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-alpha, and interlukin-8 (IL-8) in AGS gastric cancer cells. SN38 also activates nuclear factor-kappa B and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib ("Iressa", ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.
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PMID:Gefitinib ("Iressa", ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. 1572 63

Persistent colonization by Helicobacter pylori is the strongest risk factor for distal gastric adenocarcinoma, and H. pylori strains that harbor the cag pathogenicity island further augment cancer risk. The H. pylori cag island encodes a secretion system, and the product of the terminal gene in the island (CagA) is translocated into host epithelial cells after bacterial attachment, where it undergoes tyrosine phosphorylation by Src kinases and binds the eukaryotic phosphatase SHP-2. Higashi et al. now demonstrate that CagA-dependent SHP-2 activation leads to sustained activation of ERK (extracellular signal-regulated kinase), culminating in morphological changes that mimic unrestrained stimulation by growth factors. These data implicate the cag island as a key mediator of pathogenic epithelial responses that may heighten the risk for gastric cancer.
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PMID:Orchestration of aberrant epithelial signaling by Helicobacter pylori CagA. 1579 2

Autocrine stimulation via coexpression of hepatocyte growth factor (HGF) and its receptor (Met) has been reported in many human sarcomas, but few in carcinomas. In this report, we found that one gastric cancer cell line, SNU-484, among 11 gastric cell lines tested has an autocrine HGF- Met stimulation. RT-PCR, ELISA and scattering assay using MDCK cells revealed that SNU-484 cells secreted a significant amount of active HGF (about 1.25 +/- 0.41 ng/24 h/10(6) cells) into conditioned medium. Resultantly, Met in this cell line was constitutively phosphorylated. Neutralizing antibodies against HGF reduced the tyrosine phosphorylation of Met, resulting in the inhibition of cell proliferation and migration (P <0.005). To the best of our knowledge, this is the first report on autocrine HGF-Met signaling in a gastric cancer cell line. Our observations with SNU-484 cells suggest that HGF is involved in the development and/or progression of some gastric carcinoma through an autocrine mechanism.
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PMID:Presence of autocrine hepatocyte growth factor-Met signaling and its role in proliferation and migration of SNU-484 gastric cancer cell line. 1600 Aug 76

Helicobacter pylori (H. pylori) plays a crucial role in the development of gastric atrophy and cancer, and cagA-positive strains, which are universal in Japan, increase the risk of these outcomes substantially. The CagA protein is injected from attached H. pylori into gastric epithelial cells and undergoes Src-dependent tyrosine phosphorylation and activation of the eukaryotic phosphatase SHP-2. The CagA/SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. We investigated the association of a frequent single nucleotide polymorphism (SNP; JST057927; G-to-A) in the PTPN11 gene that encodes SHP-2 with gastric atrophy and gastric cancer in Japan. Gastric atrophy was assessed by measuring serum pepsinogen I and II levels. The subjects comprised 454 healthy controls (126 males; mean age, 58.4) and 202 gastric cancer cases (134 males and 68 females; mean age, 66.7). All gastric cancer cases and 250 (55%) controls were H. pylori seropositive; 179 (89%) of the gastric cancer cases had gastric atrophy compared to 137 (55%) of the H. pylori seropositive controls (p < 0.001). Among HP seropositive controls compared to the common PTPN11 G/G genotype, the odds ratio of atrophy was nonsignificantly reduced with the G/A genotype (0.70; 95% CI = 0.39-1.25) and significantly reduced with the A/A genotype (0.09; 95% CI = 0.01-0.72). Lower risk for gastric atrophy had a gene-dose association with the A allele (p = 0.01, trend test). There was a clear deficiency of the A/A genotype in those with atrophy compared to those without (1 subject in the gastric atrophy group vs. 8 in the group without). Cancer cases differed from controls in frequencies of PTPN11 G/A genotype only because of a higher prevalence of atrophy among the cancer cases. The G/A SNP in the PTPN11 gene appears to be a risk factor for gastric atrophy in subjects infected with cagA-positive H. pylori. This may explain why only a proportion of CagA-positive individuals develop gastric atrophy and gastric cancer, even though infection with cagA strains is universal in Asian countries such as Japan. The functional consequences of the G/A polymorphism remain to be elucidated.
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PMID:Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP-2 among Helicobacter pylori seropositive Japanese. 1603 4

Leptin is known to act as a growth factor through the Janus-activated kinase (JAK)/signal transducer and activator of transcription signaling pathway as well as the mitogen-activated protein kinase pathway. In this study, we showed a novel signal transduction pathway using two human gastric cancer cell lines, MKN28 and MKN74. Both gastric cancer cells expressed leptin and its receptors (Ob-R) at the protein level. We found that leptin, even at as low as 0.1 ng/mL, induced significant tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Time-course experiments revealed that phosphorylation was maximal after 5 minutes of stimulation and declined thereafter. We also revealed that tyrosine phosphorylation of EGFR induced by leptin was significantly attenuated by two inhibitors, an EGFR tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of EGFR transactivation induced by leptin is dependent on proteolytically released EGFR ligands. Leptin induced JAK2 activation and extracellular signal-regulated kinase (ERK) 1/2 activation in these gastric cancer cells, both of which occurred after the peak of EGFR transactivation. Pretreatment of gastric cancer cells with AG1478 significantly reduced the degree of phosphorylation of both JAK2 and ERK1/2. These findings indicate the involvement of EGFR transactivation in the activation of JAK2 and ERK1/2. Our results reveal that EGFR transactivation is involved in the leptin signaling pathway in gastric cancer cells, which extends the physiologic action of leptin beyond its central effects in the hypothalamus to regulate body weight.
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PMID:Transactivation of epidermal growth factor receptor is involved in leptin-induced activation of janus-activated kinase 2 and extracellular signal-regulated kinase 1/2 in human gastric cancer cells. 1623 Mar 73

CagA protein is a major virulence factor of Helicobacter pylori, which is delivered into gastric epithelial cells and elicits growth factor-like responses. Once within the cells, CagA is tyrosine phosphorylated by Src family kinases and targets host proteins required to induce the cell responses. We show that the phosphorylated CagA binds Crk adaptor proteins (Crk-II, Crk-I, and Crk-L) and that the interaction is important for the CagA-mediated host responses during H. pylori infection. H. pylori-induced scattering of gastric epithelial cells in culture was blocked by overexpression of dominant-negative Crk and by RNA interference-mediated knockdown of endogenous Crk. H. pylori infection of the gastric epithelium induced disruption of E-cadherin/catenin-containing adherens junctions, which was also dependent on CagA/Crk signaling. Furthermore, inhibition of the SoS1/H-Ras/Raf1, C3G/Rap1/B-Raf, or Dock180/Rac1/Wiskott-Aldrich syndrome protein family verprolin homologous protein pathway, all of which are involved downstream of Crk adaptors, greatly diminished the CagA-associated host responses. Thus, CagA targeting of Crk plays a central role in inducing the pleiotropic cell responses to H. pylori infection that cause several gastric diseases, including gastric cancer.
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PMID:Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. 1627 61

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.
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PMID:Protein tyrosine-phosphatase expression profiling in gastric cancer tissues. 1633 72

PRL-3 is a newly identified protein tyrosine phosphatase associated with tumor metastasis. It is over-expressed in various cancers, such as colorectal cancer, gastric cancer, and ovarian cancer, and is correlated with the progression and survival of cancers. Although PRL-3 plays a causative role in promoting cancer cell invasion and metastasis, the molecular mechanism is unknown. To investigate PRL-3's roles in tumorigenesis and signal transduction pathway, we screened the human placenta brain cDNA library with the bait of PRL-3 in yeast two-hybrid system. Then we identified integrin alpha1 as a PRL-3-interacting protein for the first time, and verified this physical association with pull-down and co-immunoprecipitation assays. Furthermore, we found that PRL-3 could down-regulate the tyrosine-phosphorylation level of integrin beta1 and increased the phosphorylation level of Erk1/2. Our present discovery will provide new clues for elucidating the molecular mechanism of PRL-3 in promoting cancer invasion and metastasis.
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PMID:Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3. 1647 76


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