Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

An important outcome of the monoclonal antibody approach for cancer-associated antigens is that cell-surface carbohydrates have been shown to be very important cancer-associated antigens. These antigens are currently classified into several groups. The first group has the sugar determinant carried by so-called type 1 chain carbohydrates, with a backbone structure composed of the Gal beta 1-->3GlcNAc beta repeating unit. The antigens in this group are utilized mainly for the diagnosis of cancers in the pancreas, biliary tract and other digestive organs. This group includes the well-known serum tumor marker, the 2 -->3 sialyl Le(a) antigen, which is detected by N19-9 and other antibodies. This group also includes DU-PAN-2, which was recently confirmed to be the sialyl Lec. The second group has the polysaccharide determinant carried by so-called type 2 chain carbohydrates, the characteristic feature of which is a backbone structure composed of the Gal beta1 -->4GlcNAc beta repeating unit. This group includes the tumor markers, sialyl SSEA-1, CSLEX-1 or sialyl Lewis X, and is used for the diagnosis of cancers originating in the lung, ovary and digestive organs. The third group has the antigenic determinant carried by the innermost core structures in O-linked carbohydrate side chains. The example of this group is the sialyl Tn antigen, which is detected in ovarian cancers. This group also includes the recently described carbohydrate determinant called Fl alpha antigen, which is frequently expressed in gastric cancer cells. Some of the antigens in the first and second groups such as sialyl Le(a) and sialyl Le(x), serve as ligands for E-selectin, a cell adhesion molecule expressed on activated human endothelial cells, and play significant roles in hematogenous metastasis of cancer.
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PMID:[Biological function of cancer-associated carbohydrate antigens]. 869 8

Helicobacter pylori is an important human pathogen which causes both gastric and duodenal ulcers and is also associated with gastric cancer and lymphoma. This microorganism has been shown to express cell surface glycoconjugates including Lewis X (Lex) and Lewis Y. These bacterial oligosaccharides are structurally similar to tumor-associated carbohydrate antigens found in mammals. In this study, we report the cloning of a novel alpha1,3-fucosyltransferase gene (HpfucT) involved in the biosynthesis of Lex within H. pylori. The deduced amino acid sequence of HpfucT consists of 478 residues with the calculated molecular mass of 56,194 daltons, which is approximately 100 amino acids longer than known mammalian alpha1,3/1,4-fucosyltransferases. The approximately 52-kDa protein encoded by HpfucT was expressed in Escherichia coli CSRDE3 cells and gave rise to alpha1,3-fucosyltransferase activity but neither alpha1,4-fucosyltransferase nor alpha1,2-fucosyltransferase activity as characterized by radiochemical assays and capillary zone electrophoresis. Truncation of the C-terminal 100 amino acids of HpFuc-T abolished the enzyme activity. An approximately 72-amino acid region of HpFuc-T exhibits significant sequence identity (40-45%) with the highly conserved C-terminal catalytic domain among known mammalian and chicken alpha1,3-fucosyltransferases. These lines of evidence indicate that the HpFuc-T represents the bacterial alpha1,3-fucosyltransferase. In addition, several structural features unique to HpFuc-T, including 10 direct repeats of seven amino acids and the lack of the transmembrane segment typical for known eukaryotic alpha1,3-fucosyltransferases, were revealed. Notably, the repeat region contains a leucine zipper motif previously demonstrated to be responsible for dimerization of various basic region-leucine zipper proteins, suggesting that the HpFuc-T protein could form dimers.
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PMID:Cloning and heterologous expression of an alpha1,3-fucosyltransferase gene from the gastric pathogen Helicobacter pylori. 926 Nov 49

Sialyl Lewis X serves as a ligand for selectins and is proposed to be implicated in hematogenous metastasis of cancers. When a cultured human breast cancer cell line, MCF-7, which does not express sialyl Lewis X, was transfected with human fucosyltransferase VI cDNA, a strong expression of sialyl Lewis X was induced on transfectant cells. The transfectant cells were found to be also reactive to the antibody NCC-ST-439, which was initially raised against human gastric cancer cells and later was shown to recognize a tumor-associated carbohydrate antigen in breast, gastric, and colon cancers. This suggested that the antigen recognized by NCC-ST-439 is closely related to sialyl Lewis X. Subsequent studies indicated that NCC-ST-439 specifically reacts to NeuAcalpha2-->3Galbeta1-->4(Fucalpha1-->3)GlcNAcbet a1-->6GalNAcalpha1 -->R, the sialyl Lewis X on the mucin GlcNAcbeta1-->6 GalNAcalpha structure. The antibody was not reactive to the conventional sialyl Lewis X determinants on straight and/or branched polylactosamine structures including NeuAcalpha2-->3Galbeta1-->4(Fucalpha1-->3)GlcNAcbet a1-->3Galbeta1-->4 Glcbeta1-->R and NeuAcalpha2-->3Galbeta1-->4(Fucalpha1-->3)GlcNAcbet a1-->6Galbeta1-->4 Glcbeta1-->R. This was in clear contrast to most of the known anti-sialyl Lewis X antibodies, which do not discriminate internal structures carrying the sialyl Lewis X determinant. On the other hand, the newly generated monoclonal antibody GSC154-27 had a specificity completely the reverse of the specificity of NCC-ST-439 in that it was strongly reactive to the conventional sialyl Lewis X determinants in straight and branched polylactosamine structures, while far less reactive to the sialyl Lewis X determinant on the mucin GlcNAcbeta1-->6GalNAcalpha core structure. A set of these two antibodies would be useful in discriminating the molecular species of sialyl Lewis X expressed by malignant cells and in studying their functional significance.
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PMID:Specific detection of sialyl Lewis X determinant carried on the mucin GlcNAcbeta1-->6GalNAcalpha core structure as a tumor-associated antigen. 964 61

Lipopolysaccharides of Helicobacter pylori express Lewis X similar to that occurring in gastric mucosa. Patients infected with H. pylori produce anti-Lewis X antibodies. The aim of this study was to examine whether anti-Lewis X antibody was associated with the development of gastric cancer, particularly intestinal type cancer. Serum sample was collected from 98 patients with early gastric cancer and 98 gender- and age-matched control subjects who underwent endoscopy. Histologically, 77 cancers were of the intestinal type. Titers of anti-H. pylori and anti-Lewis X immunoglobulin G (IgG) antibodies were assayed by enzyme-linked immunosorbent assay. The mean titer of Lewis X antibody was 0.097 in patients with gastric cancer and 0.110 in matched control subjects (not significant). In 72 H. pylori-seropositive patients with intestinal type cancer and their matched H. pylori-seropositive controls, mean titer was 0.115 and 0.107, respectively (not significant). The odds ratio for the risk of gastric cancer if Lewis X antibody was high titer was 0.93 (95% CI 0.43-2.00). The odds ratio for the risk of intestinal type gastric cancer in patients with H. pylori infection if Lewis X antibody was high titer was 1.10 (95(% CI, 0.46-2.62). Anti-Lewis X antibody does not seem to be associated with the development of gastric cancer, even the intestinal type cancer.
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PMID:Serum anti-Lewis X antibody is not elevated in patients with gastric cancer infected with Helicobacter pylori. 1091 76

Helicobacter pylori is a Gram-negative gastric pathogen causing diseases from mild gastric infections to gastric cancer. The difference in clinical outcome has been suggested to be due to strain differences. H. pylori undergoes phase variation by changing its lipopolysaccharide structure according to the environmental conditions. The O-antigen of H. pylori contains fucosylated glycans, similar to Lewis structures found in human gastric epithelium. These Lewis glycans of H. pylori have been suggested to play a role in pathogenesis in the adhesion of the bacterium to gastric epithelium. In the synthesis of fucosylated structures, GDP-l-fucose is needed as a fucose donor. Here, we cloned the two key enzymes of GDP-l-fucose synthesis, H. pylori gmd coding for GDP-d-mannose dehydratase (GMD), and gmer coding for GDP-4-keto-6-deoxy-d-mannose-3,5-epimerase/4-reductase (GMER) and expressed them in an enzymatically active form in Saccharomyces cerevisiae. The end product of these enzymes, GDP-l-fucose was used as a fucose donor in a fucosyltransferase assay converting sialyl-N-acetyllactosamine to sialyl Lewis X.
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PMID:Cloning and expression of Helicobacter pylori GDP-l-fucose synthesizing enzymes (GMD and GMER) in Saccharomyces cerevisiae. 1173

Helicobacter pylori infects over half the world's population and is a leading cause of peptic ulcer and gastric cancer. H. pylori infection results in chronic inflammation of the gastric mucosa, and progression of chronic inflammation leads to glandular atrophy and intestinal metaplasia. However, how this chronic inflammation is induced or maintained is not well known. Here, we show that chronic inflammation caused by H. pylori infection is highly correlated with de novo synthesis of peripheral lymph node addressin (PNAd) presented on high-endothelial venule (HEV)-like vessels. The number of HEV-like vessels dramatically increases as chronic inflammation progresses. We found that the PNAd is bound by L-selectin.IgM chimeric protein, and decorated by NCC-ST-439 antibody, which is suggested to recognize both nonsulfated and 6-sulfated sialyl Lewis X on core 2 branched O-glycans, and MECA-79 antibody, which reacts with 6-sulfo N-acetyllactosamine on extended core 1 O-glycans. These results indicate that PNAd on HEV-like vessels present in the gastric mucosa subsequent to H. pylori infection is similar to those on HEVs present in the secondary lymphoid organs, which are essential for lymphocyte circulation. Moreover, eradication of H. pylori is associated with the disappearance of HEV-like vessels in the gastric mucosa. By contrast, very few PNAd were found in the gastric mucosa of patients with chemical gastritis caused by nonsteroidal antiinflammatory drugs. These results strongly suggest that PNAd in HEV-like vessels plays a critical role in lymphocyte recruitment during chronic inflammation induced by H. pylori infection.
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PMID:Induction of peripheral lymph node addressin in human gastric mucosa infected by Helicobacter pylori. 1559 Nov 9

Helicobacter pylori is an important human pathogen which causes both gastric and duodenal ulcers and is associated with gastric cancer and lymphoma. This microorganism synthesizes fucosylated oligosaccharides, predominantly the Galb-1,4GlcNAc (Type II) blood group antigens Lewis X and Y, whereas a small population also expresses the Galb-1,3GlcNAc (Type I) blood group antigens Lewis A and B. These carbohydrate structures are known to mimic host cell antigens and permit the bacteria to escape from the host immune response. Here, we report the cloning and characterization of a novel H. pylori alpha-1,4 fucosyltransferase (FucT). In contrast to the family members characterized to date, this enzyme shows exclusively Type I acceptor substrate specificity. The enzyme consisting of 432 amino acids (MW 50,502 Da) was cloned using a polymerase chain reaction (PCR)-based approach. It exhibits a high degree of identity (75-87%) and similar structural features, for example, in the heptamer repeat pattern, with other H. pylori FucTs. The kinetic characterization revealed a very efficient transferase (k(cat)/Km = 229 mM(-1) s(-1)) for the Type I acceptor substrate (Gal)-1,3 GlcNAc-Lem (1). Additionally, the enzyme possesses a broad tolerance toward nonnatural Type I acceptor substrate analogs and therefore represents a valuable tool for the chemoenzymatic synthesis of Lewis A, sialyl Lewis A as well as mimetics thereof.
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PMID:Molecular cloning and functional expression of a novel Helicobacter pylori alpha-1,4 fucosyltransferase. 1600 Jun 96

Helicobacter pylori infects over half the population worldwide and is a leading cause of chronic gastritis and gastric cancer. However, the mechanism by which this organism induces inflammation and carcinogenesis is not fully understood. In the present study we used insulin-gastrin (INS-GAS) transgenic mice that fully develop gastric adenocarcinoma after infection of H. pylori-related Helicobacter felis. Histological examination revealed that more than half of those mice developed invasive adenocarcinoma after 8 months of infection. These carcinomas were stained by NCC-ST-439 and HECA-452 that recognize 6-sulfated and non-sulfated sialyl Lewis X. Lymphocytic infiltration predominantly to submucosa was observed in most H. felis-infected mice, and this was associated with the formation of peripheral lymph node addressin (PNAd) on high endothelial venule (HEV)-like vessels detected by MECA-79. Time-course analysis of gene expression by using gene microarray revealed upregulation of several inflammation-associated genes including chemokines, adhesion molecules, surfactant protein D (SP-D), and CD74 in the infected stomach. Immunohistochemical analysis demonstrated that SP-D is expressed in hyperplasia and adenocarcinoma whereas CD74 is expressed in adenocarcinoma in situ and invasive carcinoma. These results as a whole indicate that H. felis induces HEV-like vessels and inflammation-associated chemokines and chemokine receptors, followed by adenocarcinoma formation.
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PMID:A distinctive set of genes is upregulated during the inflammation-carcinoma sequence in mouse stomach infected by Helicobacter felis. 1710 21

Helicobacter pylori is a Gram-negative bacterium that infects over 50% of the world's population. This organism causes various gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer. H. pylori possesses lipopolysaccharide, which shares structural similarity to Lewis blood group antigens in gastric mucosa. Such antigenic mimicry could result in immune tolerance against antigens of this pathogen. On the other hand, H. pylori colonize gastric mucosa by utilizing adhesins, which bind Lewis blood group antigen-related carbohydrates expressed on gastric epithelial cells. In chronic gastritis, lymphocytes infiltrate the lamina propria, and such infiltration is facilitated by 6-sulfo sialyl Lewis X-capped O-glycans, peripheral lymph node addressin (PNAd), on high endothelial venule (HEV)-like vessels. The number of HEV-like vessels increases as chronic inflammation progresses. Furthermore, PNAd formed on HEV-like vessels disappear once H. pylori is eradicated. These results indicate that PNAd plays an important role in H. pylori-associated inflammation. H. pylori barely colonizes gland mucous cell-derived mucin where alpha1,4-GlcNAc-capped O-glycans exist. In vitro experiments show that alpha1,4-GlcNAc-capped O-glycans function as a natural antibiotic to inhibit H. pylori growth. We recently identified cholesterol alpha-glucosyltransferase (CHLalphaGcT) using an expression cloning strategy and showed that this enzyme is specifically inhibited by mucin-type O-glycans like those present in deeper portions of the gastric mucosa. These findings show that a battery of carbohydrates expressed in the stomach is closely associated with pathogenesis and also prevention of H. pylori-related diseases.
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PMID:Carbohydrate-dependent defense mechanisms against Helicobacter pylori infection. 1914 11

Helicobacter pylori is a Gram-negative bacterium that infects over 50% of the world's population. This organism causes various gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer. H. pylori possesses lipopolysaccharides that share structural similarity to Lewis blood group antigens in gastric mucosa. Such antigenic mimicry could result in immune tolerance against antigens of this pathogen. On the other hand, H. pylori colonizes gastric mucosa by utilizing adhesins that bind Lewis blood group antigen-related carbohydrates expressed on gastric epithelial cells. After colonization, H. pylori induces acute inflammatory responses mainly by neutrophils. This acute phase is gradually replaced by a chronic inflammatory response. In chronic gastritis, lymphocytes infiltrate the lamina propria, and such infiltration is facilitated by the interaction between L-selectin on lymphocytes and peripheral lymph node addressin (PNAd), which contains 6-sulfo sialyl Lewis X-capped O-glycans, on high endothelial venule (HEV)-like vessels. H. pylori barely colonizes gland mucous cell-derived mucin where alpha1,4-GlcNAc-capped O-glycans exist. In vitro experiments show that alpha1,4-GlcNAc-capped O-glycans function as a natural antibiotic to inhibit H. pylori growth. These findings show that distinct sets of carbohydrates expressed in the stomach are closely associated with pathogenesis and prevention of H. pylori-related diseases, providing therapeutic potentialities based on specific carbohydrate modulation.
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PMID:Roles of gastric mucin-type O-glycans in the pathogenesis of Helicobacter pylori infection. 1915 Aug 6


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