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)

Secreted glycoprotein WNTs play important roles in carcinogenesis and development. We have previously reported molecular cloning of WNT-2B/WNT-13. Here, we have isolated a novel WNT-2B isoform (WNT-2B2), in addition to the original WNT-2B isoform (WNT-2B1). WNT-2B1 and WNT-2B2 are completely different in the 5'-UTR and in the N-terminal part of the coding region. The N-terminal hydrophobic domain is contained in WNT-2B1, but not in WNT-2B2. WNT-2B1 and WNT-2B2 share the WNT-core domain, and show 87.0% amino-acid identity. We have determined the structure of the WNT-2B gene. The WNT-2B1 mRNA consists of exons 1, 2, and 4-7, while the WNT-2B2 mRNA consists of exons 3-7. WNT-2B2 was expressed in fetal brain, fetal lung, fetal kidney, caudate nucleus, testis, glioblastoma cell lines A172, SW1783, gastric cancer cell lines MKN28, MKN74, and cervical cancer cell line HeLa S3. WNT-2B1 expression level was relatively higher in fetal brain and fetal lung than in other tissues or cell lines expressing WNT-2B2. These results indicate that the WNT-2B1 and WNT-2B2 mRNAs are transcribed due to alternative splicing with distinct expression profile. This is the first report on the WNT isoforms derived from the same gene due to alternative splicing.
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PMID:Alternative splicing of the WNT-2B/WNT-13 gene. 1094 66

Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil (5-FU). TS has a polymorphic repeated sequence in the 5'-UTR and the polymorphism is associated with TS protein expression. TS polymorphism has been reported to link with the efficacy of 5-FU-based chemotherapy in colorectal cancer. In this study, we examined whether the association among TS polymorphism, TS mRNA expression and TS protein expression is also observed in gastric cancer tissues and whether the TS polymorphism is a prognostic factor for patients with gastric cancer. We quantified TS mRNA isolated from 115 gastric cancer tissues by real-time reverse transcription PCR and TS protein in 72 available samples by the fluoro-dUMP binding assay. These values were compared with TS genotypes of the samples determined by a PCR assay. The tumor with the 3R/3R genotype had higher TS protein expression than that with the 2R/3R genotype, although there is no association between the TS genotype and mRNA expression. The result suggests that mRNA translation is responsible for the genotype-dependent difference of TS protein expression, as is consistent with our previous observation in colorectal cancer. This association encouraged us to further examine the link of the TS genotype with the stage of disease and the prognosis of the patients. The clinicopathological analysis showed that gastric cancers with the 3R/3R genotype are at a more advanced stage than those with the combined 2R/2R and 2R/3R genotype. We observed a longer survival in those patients with the combined 2R/2R and 2R/3R genotype, compared with the 3R/3R genotype, although it did not reach significance when the patients who had received the oral fluoropyrimidines therapy were analyzed. These results warrant further large-scale clinical study of the role of the TS genotyping for the prediction of efficacy using 5-FU-based chemotherapy and prognosis in gastric cancer.
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PMID:Association of thymidylate synthase gene polymorphism with its mRNA and protein expression and with prognosis in gastric cancer. 1253

Thymidylate synthetase (TS) and methylenetetrahydrofolate reductase (MTHFR) are major enzymes in the metabolism of folates, involved in DNA 'breaks', instability and hypomethylation. To investigate the possible relations between the TS 3'-UTR and MTHFR C677T polymorphisms and environmental factors impacting on risk of esophageal and stomach cancers, we conducted a case-control study in a high incidence region of China for these cancers. We recruited 138 esophageal and 155 stomach cancer cases, and 223 controls. The TS 3' -UTR and MTHFR C677T genotypes were detected by RFLP assay, using PCR products. The frequency of the -6 bp homozygous TS 3' -UTR genotype was 37.7 % in controls, higher than in Caucasians, although the present distribution was not in Hardy-Weinberg equilibrium. Ever-smoking with the -6 bp/-6 bp TS genotype elevated the ORs (2.61, 1.24-5.49; 3.54, 1.60-7.82) for cases of esophageal and stomach cancers, respectively, when compared with never-smoking with the +6 bp/+6 bp and +6 bp/-6 bp genotypes. No combination between the TS and MTHFR genotypes gave increased ORs. The present results suggest that TS polymorphism may modify the risk of esophageal and stomach cancer with smoking, pointing to the necessity for further investigations with information on folate and methionine intake with a larger population.
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PMID:Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking. 1524 14

We investigated in a case-control study a possible role of thymidylate synthase gene (TS) polymorphisms for gastric cancer susceptibility. Lymphocyte genomic DNA from 134 Italian gastric cancer patients and 139 controls was used for genotyping two polymorphisms in the TS 5'-untranslated region (5'-UTR); a double (2R) or triple (3R) 28-bp repeat and a G/C polymorphism within the triple repeats allele (3G allele). Samples were also genotyped at a 6-bp deletion/insertion (del6 or ins6) polymorphism at position 1494 in the TS 3'-untranslated region (3'-UTR). Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with the disease. The global allelic distribution was in Hardy-Weinberg equilibrium. Genotypes with the 3G allele (2R/3G, 3C/3G, 3G/3G) were significantly more frequent in patients than controls and were associated with gastric cancer risk (OR = 2.06; 95% CI = 1.26-3.35). A significant risk was also observed for carriers of the del6 allele in the 3'-UTR. Odds ratios for combined 3G-del6/ins6 and 3G-del6/del6 genotypes were 2.59 (95% CI = 1.36-4.94) and 2.81 (95% CI = 1.22-6.64), respectively. The 3G-del6 haplotype showed a significant association with the disease (p = 0.01). Polymorphisms in the TS gene may contribute to gastric cancer susceptibility and this finding deserve further investigation in the context of novel strategies for gastric cancer prevention. In vitro, 3G genotypes have been related to high TS mRNA expression, which may underlie one of the possible etiologic mechanisms.
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PMID:Association of thymidylate synthase polymorphisms with gastric cancer susceptibility. 1538 66

The improved IGCR (In-Gel Competitive Reassociation) method was applied to the analysis of human gastric cancer genomic DNA to identify its alterations, and it appeared that the IGCR library contained a fragment of 3'-untranslated region (3' UTR) of G-protein coupled receptor 30 (GPR30) mRNA. When we searched genomic DNA pairs of gastric cancer patients with this IGCR clone, we found the deletion polymorphism with or without 2 bp (Cytosine and Thymine; CT). We confirmed the existence of a novel mRNA in GPR30 3'UTR by northern blotting, cloned this novel mRNA and named it Leucine Rich Protein in GPR30 3'UTR (LERGU). The EST database search gave one alternative splicing form in this 3' UTR, which was named as LERGU-1. A novel alternative splicing form of this mRNA was also identified from the stomach total RNA, which was named LERGU-2. The LERGU mRNA was also detected in eight gastric cancer cell lines, but GPR30 mRNA scarcely existed. Furthermore, we detected the 2 bp-deletion form in genomic DNAs and mRNAs derived from gastric cancers, but not in other type cancers. Since the 2 bp-deletion position on LERGU corresponds to its alternative splicing site, this deletion may produce a frame-shifted protein. Overall, our findings suggest that a mutation or disappearance of the normal LERGU protein may have a function in the development of gastric cancer.
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PMID:Cloning of novel LERGU mRNAs in GPR30 3' untranslated region and detection of 2 bp-deletion polymorphism in gastric cancer. 1577 23

WNT, Hedgehog and Notch signaling pathways network together during carcinogenesis and embryogenesis. WNT3A-WNT9A (WNT14) locus at chromosome 1q42.13 and WNT3-WNT9B (WNT14B) locus at chromosome 17q21.31 are paralogous regions within the human genome. WNT9A mRNA is expressed in various types of human cancer, such as gastric cancer, pancreatic cancer, and breast cancer. In addition, Wnt9a gene is implicated in chondrogenesis and joint formation during embryogenesis. Here we identified and characterized rat Wnt9a gene by using bioinformatics. Rat Wnt9a gene, consisting of four exons, was located within AC121055.4 and AC133374.2 genome sequences. Rat Wnt9a protein (365 aa) with N-terminal signal peptide, 24 Cys residues and one Asn-linked glycosylation site showed 100%, 98.1% and 82.5% total amino-acid identity with mouse Wnt9a, human WNT9A and chicken wnt9a, respectively. Exonic regions except 3'-UTR were well conserved between human WNT9A and rodent Wnt9a genes; however, 5'-flanking promoter region was not well conserved. Transcription-factor-binding sites conserved between human WNT9A and rodent Wnt9a 5'-flanking promoter regions were not identified by using the Match program. Although the amino-acid sequence was highly conserved among mammalian Wnt9a orthologs, the 5'-flanking promoter region was significantly divergent between human WNT9A and rodent Wnt9a genes. This is the first report on rat Wnt9a gene as well as on comparative genomics for Wnt9a orthologs.
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PMID:Comparative genomics on Wnt9a orthologs. 1580 69

Fruits and certain vegetables have a protective effect on gastric cancer (GC) and folate is one of the nutrients in fruits and vegetables. We hypothesized that the polymorphisms of thymidylate synthase (TYMS) gene involved in folate metabolism are associated with GC risk. In a population-based case-control study of 337 GC cases and 326 controls, frequency-matched by age, sex and residential areas in a southern Chinese population, we genotyped the 28 bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER) and the 6 bp deletion/insertion at bp 1494 in the TYMS 3'-untranslated region (TS3'UTR). We found that although the TSER polymorphism had no main effect on GC risk, the TS3'UTR 6 bp/6 bp genotype was associated with a significantly increased risk of GC [adjusted odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.18-3.25], especially the non-cardiac gastric cancer (2.16, 1.22-3.82), compared with the 0 bp/0 bp genotype. However, when we evaluated these two polymorphisms together and used the combined genotype with zero variant allele (TSER 2R and TS3'UTR 6 bp variant alleles) as the reference, we found that the combined genotype with three or four variant alleles was associated with a significantly increased risk of GC (2.06, 1.12-3.79), especially the non-cardiac gastric cancer (2.33, 1.19-4.59), and this significant association was more pronounced among older women (>60 years old), non-smokers, and never tea drinkers. In conclusion, the TYMS polymorphisms, especially the TS3'UTR polymorphism, are associated with GC risk, especially the non-cardiac gastric cancer, and the TSER 2R and TS3'UTR 6 bp alleles may jointly play a role in the etiology of GC in the southern Chinese population. Larger studies are warranted to verify these findings.
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PMID:Polymorphisms of thymidylate synthase in the 5'- and 3'-untranslated regions associated with risk of gastric cancer in South China: a case-control analysis. 1593 32

To elucidate the genetic events associated with gastric cancer, 124,704 cDNA clones were collected from 37 human gastric cDNA libraries, including 20 full-length enriched cDNA libraries of gastric cancer cell lines and tissues from Korean patients. An analysis of the collected ESTs revealed that 97,930 high-quality ESTs coalesced into 13,001 clusters, of which 11,135 clusters (85.6%) were annotated to known ESTs. The analysis of the full-length cDNAs also revealed that 4862 clusters (51.7%) contained at least one putative full-length cDNA clone with an initiation codon, with the average length of the 5' UTR of 140 bp. A large number appear to have a diverse transcription start site (TSS). An examination of the TSS of some genes, such as TEGT and GAPD, using 5' RACE revealed that the predicted TSSs are actually found in human gastric cancer cells and that several TSSs differ depending on the specific gastric cell line. Furthermore, of the human gastric ESTs, 766 genes (9.5%) were present as putative alternatively spliced variants. Confirmation of the predicted spliced isoforms using RT-PCR showed that the predicted isoforms exist in gastric cancer cells and some isoforms coexist in gastric cell lines. These results provide potentially useful information for elucidating the molecular mechanisms associated with gastric oncogenesis.
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PMID:Transcriptome analysis of human gastric cancer. 1634 74

To investigate the relationship between polymorphism in the 3'-untranslated region (3'-UTR) of the thymidylate synthase (TS) gene and sensitivity of gastric cancer to 5-fluorouracil (5-FU)-based chemotherapy, 106 cases of advanced gastric cancer were analyzed. All patients were treated with 5-FU-based chemotherapy; DNA from peripheral blood leukocytes was obtained before therapy. TS 3'-UTR genotypes were detected by PCR-RFLP. Polymorphism in the TS 3'-UTR can be classified into three groups according to the presence or absence of a 6 bp nucleotide fragment: the -6/-6 bp, -6/+6 bp and +6/+6 bp groups. The response rate of the -6/-6 bp and -6/+6 bp groups was found to be significantly higher than the +6/+6 bp group. These results show that the presence of the TS 3'-UTR 6 bp nucleotide fragment can be correlated with the sensitivity of gastric cancer to 5-FU-based chemotherapy, and that the TS 3'-UTR polymorphism profile can be used to guide the choice of 5-FU-based chemotherapy in advanced gastric cancer.
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PMID:Polymorphism in the 3'-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy. 1642 79

Stem cells are characterized by self-renewal and multipotency to produce multiple lineages of progenitor and differentiated cells. PROM1 gene encodes CD133 protein, which is a cell surface marker of hematopoietic stem cells, prostatic epithelial stem cells, pancreatic stem cells, leukemic stem cells, liver cancer stem cells, and colorectal cancer stem cells. Here, comparative integromics analyses on PROM1 orthologs were performed. Human PROM1 RefSeq NM_006017.1 was a truncated transcript, while AK027422.1 was the representative human PROM1 cDNA. Chimpanzee PROM1 gene, consisting of 27 exons, was identified within NW_001234057.1 genome sequence. Chimpanzee 5-transmembrane protein CD133 showed 99.2% and 60.9% total-amino-acid identity with human and mouse CD133 orthologs, respectively. Only 2 of 8 Asn-linked glycosylation sites in primate CD133 orthologs were conserved in rodent CD133 orthologs. Comparative proteomics revealed that CD133 orthologs were relatively divergent between primates and rodents. PROM1 mRNA was expressed in human embryonic stem (ES) cells, trachea, small intestine, NT2 cells, diffuse-type gastric cancer, and colorectal cancer. Human PROM1 mRNA transcribed from exon 1A was the major transcript. Comparative genomics revealed that the region around exon 1A corresponding to 5'-UTR of human PROM1 mRNA was not conserved in mouse and rat. Intron 2 of PROM1 orthologs was relatively well conserved among mammals. Tandem TCF/LEF-binding sites with 7-bp spacing within intron 2 were conserved among human, chimpanzee, mouse, and rat PROM1 orthologs. Together these facts indicate that canonical WNT signaling activation is implicated in CD133 expression in ES cells, adult stem cells, and cancer stem cells.
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PMID:Comparative genomics on PROM1 gene encoding stem cell marker CD133. 1748 31


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