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Query: UNIPROT:P06889 (Mol)
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Drosophila prickle is implicated in tissue polarity or planar polarity. Here, human PRICKLE1 gene corresponding to FLJ31937 cDNA and human PRICKLE2 gene corresponding to DKFZp686D143 cDNA were identified to be homologous to Drosophila prickle gene by using bioinformatics. PRICKLE1 gene was mapped to human chromosome 12p11-q12, and PRICKLE2 gene was mapped to human chromosome 3p14. Mouse Prickle1 and Prickle2 genes were next identified in mouse genome draft sequences NW_000106.1 and NW_000262.1, respectively. Human PRICKLE1, PRICKLE2, Xenopus Prickle, and Drosophila prickle were homologous in the PET domain, three LIM domains, and the C-terminal Prickle homologous (PKH) domain. LMO6 and TESTIN, containing the PET domain and three LIM domains, were found to lack the PKH domain. Therefore, PRICKLE1 and PRICKLE2 rather than LMO6 and TESTIN were found to be human homologs of Drosophila prickle. PRICKLE1 and PRICKLE2 mRNAs were expressed together in brain, eye and testis. PRICKLE1 mRNA was expressed in fetal heart and hematological malignancies, while PRICKLE2 mRNA in fetal brain, adult cartilage, pancreatic islet, gastric cancer with signet-ring cell features, and uterus tumors. Because tissue polarity genes frizzled, dishevelled, flamingo, and Vang are evolutionary and functionary conserved from Drosophila to human, PRICKLE1 and PRICKLE2 might be implicated in the localization of Frizzled and Dishevelled proteins, just like Drosophila prickle. This is the first report on identification and characterization of human PRICKLE1, PRICKLE2, mouse Prickle1, and Prickle2 genes.
Int J Mol Med 2003 Feb
PMID:Identification and characterization of human PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2 genes homologous to Drosophila tissue polarity gene prickle. 1252 87

Although debates still exist whether Helicobacter pylori infection is really class I carcinogen or not, H. pylori has been known to provoke precancerous lesions like gastric adenoma and chronic atrophic gastritis with intestinal metaplasia as well as gastric cancer. Chronic persistent, uncontrolled gastric inflammations are possible basis for ensuing gastric carcinogenesis and H. pylori infection increased COX-2 expressions, which might be the one of the mechanisms leading to gastric cancer. To know the implication of long-term treatment of antiinflammatory drugs, rebamipide or nimesulide, on H. pylori-associated gastric carcinogenesis, we infected C57BL/6 mice with H. pylori, especially after MNU administration to promote carcinogenesis and the effects of the long-term administration of rebamipide or nimesulide were evaluated. C57BL/6 mice were sacrificed 50 weeks after H. pylori infection. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels and mRNA transcripts of various mouse cytokines and chemokines, and NF-kappaB binding activities, and finally the presence of gastric adenocarcinoma were compared between H. pylori infected group (HP), and H. pylori infected group administered with long-term rebamipide containing pellet diets (HPR) or nimesulide mixed pellets (HPN). Gastric mucosal expressions of ICAM-1, HCAM, MMP, and transcriptional regulations of NF-kappaB binding were all significantly decreased in HPR group than in HP group. Multi-probe RNase protection assay showed the significantly decreased mRNA levels of apoptosis related genes and various cytokines genes like IFN-gamma, RANTES, TNF-alpha, TNFR p75, IL-1beta in HPR group. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not changed between HP and HPR group, but significantly decreased in HPN group, suggesting the chemoprevention of H. pylori-associated gastric carcinogenesis by COX-2 inhibition. Long-term administration of antiinflammatory drugs should be considered in the treatment of H. pylori since they showed the molecular and biologic advantages with possible chemopreventive effect against H. pylori-associated gastric carcinogenesis. If the final concrete proof showing the causal relationship between H. pylori infection and gastric carcinogenesis could be obtained, that will shed new light on chemoprevention of gastric cancer, that is, that gastric cancer could be prevented through either the eradication of H. pylori or lessening the inflammation provoked by H. pylori infection in high risk group.
J Biochem Mol Biol 2003 Jan 31
PMID:Chemoprevention of Helicobacter pylori-associated gastric carcinogenesis in a mouse model: is it possible? 1254 79

Gastric cancer carries a poor prognosis and is the second most frequent cause of cancer-related death worldwide. In spite of the clinical importance of this tumour entity, only a few fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) studies have been published on gastric carcinomas. The aim of this study was to characterise the FDG uptake of gastric carcinomas by relating it to the histopathological properties of the tumours. Within this context, we focussed particularly on the microscopic growth type according to Lauren since our preliminary observations indicated low FDG accumulation in the non-intestinal growth type compared with the intestinal type. Forty patients with locally advanced gastric carcinomas and ten control subjects were studied by FDG PET (300 MBq i.v., emission scan: 40 min p.i., one bed position, measured transmission, filtered back-projection). Detectability of the tumours was qualitatively assessed by two independent observers. For quantitative analysis the regional tumour uptake was measured by standardised uptake values (SUV normalised to the body surface area) using a region of interest technique. Qualitative and quantitative analyses were performed with respect to the microscopic growth type according to Lauren (intestinal type vs non-intestinal type). Other histopathological characteristics were also assessed: mucus content, grading, tumour extension and tumour location. In 36 patients the survival rates were compared for detectable vs non-detectable tumours and for tumour FDG uptake above and below the median. Only 24 of the 40 locally advanced gastric carcinomas (60%) were detected by FDG PET. The detection rate for tumours of the intestinal type was significantly higher than that for tumours of the non-intestinal type (83% vs 41%, P=0.01). Only 2/18 intestinal type tumours contained extracellular or intracellular mucus whereas 17/22 non-intestinal tumours did so (P<0.01). The mean SUV was significantly different between the intestinal type and the non-intestinal type (6.7+/-3.4 vs 4.8+/-2.8, P=0.03), between non-mucus-containing tumours and mucus-containing tumours (7.2+/-3.2 vs 3.9+/-2.1, P<0.01) and between grade 2 tumours and grade 3 tumours (7.4+/-2.3 vs 5.2+/-3.3, P=0.02). The survival rate was not significantly different in patients with detectable tumours on FDG PET and patients with non-detectable tumours (P=0.85). It is concluded that advanced malignant tumours with a poor prognosis may show low FDG uptake due to special histopathological characteristics. The overall low detection rate of gastric carcinomas is attributable to the frequent occurrence of diffusely growing and mucus-containing tumour types. This may limit the value of FDG PET for diagnosis and therapy monitoring in patients with gastric carcinomas. Furthermore, the intensity of tumour FDG uptake is not predictive of survival in gastric carcinomas.
Eur J Nucl Med Mol Imaging 2003 Feb
PMID:FDG PET imaging of locally advanced gastric carcinomas: correlation with endoscopic and histopathological findings. 1255 48

Human SNAIL1 (SNAI1) protein encoded by SNAI1/SNA gene represses transcription of E-cadherin/CDH1 gene. Human SNAIL2 (SNAI2) protein encoded by SNAI2/SLUG gene induces the first phase of epithelial-mesenchymal transition (EMT), including desmosome dissociation, cell spreading, and initiation of cell separation. Here, we have identified human SNAIL3 (SNAI3) gene using bioinformatics. Human SNAI3 gene, consisting of at least three exons, spans around the nucleotide position 320214-328221 of human reference genomic contig NT_010404.8 in the reverse orientation. SNAI3 gene, was located between KIAA0233 gene and CBFA2T3 gene in human chromosome 16q24.3, a region affected in breast cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, and therapy-related myeloid leukemia with t(16;21)(q24;q22) translocation. Human SNAI3 gene was found to encode 292-amino-acid polypeptide with the N-terminal SNAG domain and five zinc finger domains. N-terminal SNAG domain was identified in zinc finger proteins SNAI1, SNAI2, SNAI3, SCRATCH (SCRT1), GFI1, and GFI1B. ATP/GTP binding site was identified in SCRT1, GFI1 and GFI1B, but not in SNAI1, SNAI2 and SNAI3. Phylogenetic analysis of human zinc finger proteins with SNAG domain revealed that SNAI1, SNAI2 and SNAI3 were more closely related. These results clearly indicate that SNAI1, SNAI2 and SNAI3 constitute a subfamily among SNAG zinc-finger proteins. Human SNAI3 mRNA was expressed in skin melanotic melanoma, lung epidermoid carcinoma, and germ cell tumor. Because SNAG zinc-finger proteins are transcriptional repressors implicated in carcinogenesis and embryogenesis, SNAI3 gene might be a potent target of pharmacogenomics in the field of oncology and regenerative medicine.
Int J Mol Med 2003 Mar
PMID:Identification and characterization of human SNAIL3 (SNAI3) gene in silico. 1257 45

E-cadherin is involved in the formation of cell-junctions and the maintenance of epithelial integrity. Direct evidence of E-cadherin mutations triggering tumorigenesis has come from the finding of inactivating germline mutations of the gene (CDH1) in hereditary diffuse gastric cancer (HDGC). We screened a series of 66 young gastric cancer probands for germline CDH1 mutations, and two novel missense alterations together with an intronic variant were identified. We then analysed the functional significance of the two exonic missense variants found here as well as a third germline missense variant that we previously identified in a HGDC family. cDNAs encoding either the wild-type protein or mutant forms of E-cadherin were stably transfected into CHO (Chinese hamster ovary) E-cadherin-negative cells. Transfected cell-lines were characterized in terms of aggregation, motility and invasion. We show that a proportion of apparently sporadic early-onset diffuse gastric carcinomas are associated with germline alterations of the E-cadherin gene. We also demonstrate that a proportion of missense variants are associated with significant functional consequences, suggesting that our cell model can be used as an adjunct in deciding on the potential pathogenic role of identified E-cadherin germline alterations.
Hum Mol Genet 2003 Mar 01
PMID:Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. 1258 4

Chronic infection with Helicobacter pylori causes peptic ulcers, gastric cancer and lymphoma. We evaluated the inhibitory effects of the probiotic Lactobacillus acidophilus DDS-1J, the antibiotic clarithromycin and the natural antioxidants garcinol and Protykin (containing 50% trans-resveratrol) on Helicobacter pylori strain ATCC 49503. The findings of this study indicate that Lactobacillus acidophilus DDS-1J exerts a growth inhibitory effect on H. pylori at a ratio of 1:1 or higher in vitro. In the case of clarithromycin, garcinol and resveratrol, the bactericidal effect is time and concentration dependent. Clarithromycin completely inhibited growth at > or = 62.5 microg/ml at 6 h and at > or = 31.5 microg/ml at 12 h. For garcinol the highest concentration needed for complete inhibition was 31.5 microg/ml at 6 h and 3.9 microg/ml after 12 h incubation. For resveratrol, significant inhibition was noted at 1000 microg/ml at 12 h only. The bactericidal effect of garcinol was reduced by the addition of resveratrol at all concentrations < or = 125 microg/ml at 6 and 12 h. We conclude from this study that Lactobacillus acidophilus DDS-1J inhibits H. pylori at 1:1 and higher ratios. Also, between the two antioxidants, garcinol is much more potent than resveratrol as a bactericidal agent against H. pylori, and that resveratrol may antagonize this effect. Finally, our study showed equivalent or better bactericidal activity of garcinol compared to clarithromycin against H. pylori at 6 and 12 h incubation, indicating a potential role for this antioxidant in treatment for H. pylori infection.
Mol Cell Biochem 2003 Jan
PMID:The bactericidal effects of Lactobacillus acidophilus, garcinol and Protykin compared to clarithromycin, on Helicobacter pylori. 1261 86

Knowledge regarding the genetic basis of hereditary diffuse gastric cancer has greatly increased in the past 4 years, namely due to the discovery of segregating germline mutations in the gene coding for E-cadherin, within families with this cancer predisposing syndrome. Members of hereditary diffuse gastric cancer families have predominantly high predisposition to develop diffuse carcinomas of the stomach but can also be associated with an elevate risk for other types of cancer, namely lobular breast carcinoma. In this review, we focus on the epidemiology, pathology and genetics of gastric cancer, describe families, E-cadherin mutations, and suggest alternative candidate genes underlying the hereditary diffuse gastric cancer syndrome. This knowledge is a fundamental step towards accurate genetic counselling, in which a highly specialized presymptomatic therapeutic intervention should be offered.
Expert Rev Mol Diagn 2003 Mar
PMID:Genetic screening for hereditary diffuse gastric cancer. 1264 96

Phage display technology is now well established as an important experimental approach in designing new reagents for diagnosis of diseases and development of novel vaccines. Aiming at identifying possible immunogenic mimotopes of gastric cancer-associated antigen, we used a monoclonal antibody against gastric cancer, named monoclonal antibody MG7, to screen two phage-displayed nanopeptide libraries. All selected phages were used to immunize BALB/c mice separately. By immunohistochemical staining the tissue sections with the immunized mice sera, we identified one phage that induced gastric cancer-specific antibody response. Consistent with our reported results before, we demonstrate that specific immunogenic epitopes can be isolated by screening phage-displayed library even when natural antigens are not readily available.
Mol Cancer Ther 2003 Mar
PMID:Selection and identification of mimic epitopes for gastric cancer-associated antigen MG7 Ag. 1265 25

FGFR2 is an oncogene amplified in diffuse-type gastric cancer, and WDR11 is a tumor suppressor gene disrupted in glial tumor. WDR11-FGFR2 locus on human chromosome 10q26 is one of cancer-related recombination hot spots. In this study, we investigated recombination and nucleotide substitution around the WDR11-FGFR2 locus during evolution by using bioinformatics. Inter-chromosomal comparison revealed that the human BAG3-FGFR2-TACC2 region was paralogous to the human BAG4-FGFR1-TACC1 region. Inter-specific comparison on the BAG3-FGFR2-TACC2 region revealed that HTPAPL-WDR11-FGFR2 locus containing species-specific insertion or deletion was one of evolutionary recombination hot spots. Between human and mouse, coding-region nucleotide substitution rate and amino-acid substitution rate were significantly lower in the HTPAPL-WDR11-FGFR2 locus than in the surrounding locus (P<0.0001). The HTPAPL-WDR11-FGFR2 locus was more susceptible to recombination than to nucleotide substitution. Detailed comparison of human and mouse genomes could identify evolutionary recombination hot spots overlooked during gross comparison of human and mouse genomes. Because DNA double-strand break is the initial step in various types of recombination including chromosomal translocation, rearrangement, deletion, gene amplification, retroviral integration and retrotransposition, it is reasonable that the HTPAPL-WDR11-FGFR2 locus is the recombination hot spot during evolution as well as during carcinogenesis. Therefore, comparative genomics might be applicable to identification of recombination hot spots and genes related to cancer.
Int J Mol Med 2003 May
PMID:Recombination cluster around FGFR2-WDR11-HTPAPL locus on human chromosome 10q26. 1268 93

Microarray analyses combined with laser-capture microdissection have been applied for risk assessments of gastric cancer as well as for identification of novel genes associated with gastric cancer. EST AA393089 derived from an unknown gene has been reported to be frequently down-regulated in intestinal-type gastric cancer. Here, we identified and characterized the gene corresponding to EST AA393089 by using bioinformatics. EST AA393089 overlapped with BC016047 cDNA, and BC016047 overlapped with EST BM821052. Because the mRNA determined by assembling BM821052 and BC016047 was derived from a novel Claudin (CLDN) family gene, the gene corresponding to EST AA393089 was designated CLDN23. Human CLDN23 mRNA was expressed in germinal center B cells, placenta, stomach as well as in colon tumor. Mouse AK009330 and AK037108 cDNAs were derived from mouse Cldn23 gene. Human CLDN23 (292 aa) and mouse Cldn23 (296 aa) were four-transmembrane proteins, showing 79.5% total-amino-acid identity. WWCC motif, defined by W-X(17-22)-W-X(2)-C-X(8-10)-C, was conserved among four-transmembrane proteins of CLDN family. CLDN23 gene, linked to MFHAS1 and PPP1R3B genes, was mapped to human chromosome 8p23.1. CLDN21, CLDN22, and CLDN24 genes were also identified in this study. CLDN21 and CLDN22 genes were located within human genomic contig NT_022792.13. CLDN24 gene on human chromosome 11q23 was located within human genomic contig NT_033899.3. Among 23 CLDN family genes within the human genome, CLDN1 and CLDN16 genes were clustered on human chromosome 3q28, CLDN3 and CLDN4 on 7q11, CLDN6 and CLDN9 on 16p13.3, CLDN8 and CLDN17 on 21q22.11, CLDN21 and CLDN22 on 4q35.1. This is the first report on comprehensive characterization of CLDN23 gene, a candidate tumor suppressor gene implicated in intestinal-type gastric cancer.
Int J Mol Med 2003 Jun
PMID:CLDN23 gene, frequently down-regulated in intestinal-type gastric cancer, is a novel member of CLAUDIN gene family. 1273 7


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