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)

To identify germline E-cadherin mutations responsible for the predisposition to diffuse gastric cancer (DGC) among the Japanese, we screened 17 patients with familial aggregation of gastric cancer by sequencing analysis. All the patients were diagnosed with DGC and had at least 1 sibling with gastric cancer. Two novel E-cadherin gene variants were detected. One was detected in 1 patient only and associated with an amino acid substitution (Val/Met) at codon 832 in the region essential for binding to beta-catenin. The M832 variant was detected not only in the proband but also in 2 other gastric cancer patients in the family. Immunohistochemical analysis of gastric cancer tissue from the proband revealed that E-cadherin expression was markedly reduced and beta-catenin expression was also reduced in cancer cells. However, no significant difference in the activity of beta-catenin binding was detected between the M832 variant and V832 wild-type E-cadherin in immunofluorescence and immunoprecipitation/Western blot analyses. The other was detected in 5 patients and was located in the splice donor site (IVS1+6T/C); however, RT-PCR analysis indicated that the IVS+6C variant did not cause an aberrant splicing. Thus, the M832 variant could be a germline mutation causative of familial aggregation of DGC, although further functional studies are needed to understand the pathogenic significance of this variant.
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PMID:E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer. 1221 71

WNT signaling molecules, playing key roles in embryogenesis and carcinogenesis, are potent targets for regenerative medicine and clinical oncology. We have previously cloned and characterized the human orthologue of mouse proto-oncogene Wnt-10b using bioinformatics and cDNA-PCR. Human WNT10B is moderately expressed in MKN45 and MKN74 cells derived from human gastric cancer, and is up-regulated by tumor necrosis factor alpha (TNFalpha) in MKN45 cells. Here, expression and regulation of WNT10B in human cancer other than gastric cancer were investigated using cDNA-PCR. WNT10B mRNA was expressed in the majority of squamous cell carcinoma cell lines derived from esophageal cancer and cervical cancer. WNT10B mRNA was relatively highly expressed in TE3, TE6, TE10, TE11 (esophageal cancer), Hs700T (pancreatic cancer), SKG-IIIa, HeLa S3 (cervical cancer), and T-47D (breast cancer). Expression of WNT10B mRNA was up-regulated by beta-estradiol in MCF-7 cells expressing estrogen receptors. Expression of WNT10B mRNA was down-regulated by all-trans retinoic acid in NT2 cells with the potential of self renewal and neuronal differentiation. WNT10B might be implicated in self renewal of stem cells as well as in carcinogenesis through activation of the WNT - beta-catenin pathway.
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PMID:Expression and regulation of WNT10B in human cancer: up-regulation of WNT10B in MCF-7 cells by beta-estradiol and down-regulation of WNT10B in NT2 cells by retinoic acid. 1223 2

WNT signals are transduced through seven-transmembrane-type WNT receptors encoded by Frizzled (FZD) genes to the beta-catenin - TCF pathway, the JNK pathway or the Ca2+-releasing pathway. WNT signaling molecules are potent targets for diagnosis of cancer (susceptibility, metastasis, and prognosis), for prevention and treatment of cancer, and for regenerative medicine or tissue engineering. We have so far cloned and characterized human WNT signaling molecules WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14, WNT14B/WNT15, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, FRAT1, FRAT2, NKD1, NKD2, VANGL1/STB2, ARHU/WRCH1, ARHV/WRCH2, GIPC2, GIPC3, betaTRCP2/FBXW1B, SOX17, and TCF-3 using bioinformatics, cDNA-library screening, and cDNA-PCR. Here, expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer were investigated. WNT7A was highly expressed in fetal lung, adult testis, lymph node, and peripheral blood leukocytes. WNT7A was relatively highly expressed in temporal lobe, occipital lobe, parietal lobe, paracentral gyrus of cerebral cortex, caudate nucleus, hippocampus, medulla oblongata and putamen within adult brain. WNT7A was highly expressed in SW480 (colorectal cancer), BxPC-3 and Hs766T (pancreatic cancer), and was also expressed in MKN7 and MKN45 (gastric cancer). WNT7B rather than WNT7A was expressed in MCF-7 (breast cancer) and NT2 (embryonal tumor). beta-estradiol did not affect expression levels of WNT7A and WNT7B in MCF-7 cells. WNT7B, but not WNT7A, was slightly up-regulated by all-trans retinoic acid in NT2 cells.
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PMID:Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer. 1223 32

We investigated the frequency and mechanism of beta-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the beta-catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or beta-catenin, and Tcf-4 was highly expressed in these cell lines with upregulated signaling. Nuclear beta-catenin was observed not only in the signaling-activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling-upregulated gastric cancer cell lines with intact APC and beta-catenin suggests the involvement of other mechanisms than mutations of APC or beta-catenin.
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PMID:Analysis of the beta-catenin/T cell factor signaling pathway in 36 gastrointestinal and liver cancer cells. 1246 Apr 62

WNT signals play key roles in carcinogenesis and embryogenesis through the specification of cell fate and polarity. Dishevelled (DVL) proteins are WNT signaling molecules implicated in beta-catenin pathway and PCP pathway. Xenopus Dapper and Frodo are Dvl-binding proteins, showing 89.8% total-amino-acid identity. Here, we identified and characterized human homologs of Xenopus Dapper and Frodo using bioinformatics. Human DAPPER1 gene was located within human genome draft sequence NT_025892.9 (nucleotide position 39378960-39387891 in the forward orientation), and human DAPPER2 gene within NT_007302.10 (nucleotide position 660279-672480 in the reverse orientation). DAPPER1 (799-amino-acids) and DAPPER2 (774-amino-acids) showed 28.8% total-amino-acid identity. Seven DAPPER homologous (DAPH) domains, including DAPH2 (leucine zipper), DAPH3 (serine rich) and DAPH7 (PDZ binding), were conserved between DAPPER1 and DAPPER2. Phylogenetic analysis of vertebrate Dapper proteins revealed that Xenopus Dapper and Frodo are orthologs of human DAPPER1. DAPPER1 mRNA was expressed in amnion, fetal brain, eye, heart, adult brain medulla, gastric cancer (signet ring cell features), RER+ colon tumor, acute lymphoblastic leukemia, germ cell tumor, chondrosarcoma, and parathyroid tumor. DAPPER2 mRNA was expressed in placenta, genitourinary tract tumor, and endometrial adenocarcinoma. DAPPER1 and DAPPER2 genes were mapped to human chromosome 14q22.3 and 6q27, respectively. Human chromosome 14q22.3 is deleted in astrocytoma, while human chromosome 6q27 is deleted in breast, ovarian, and gastric cancer. Based on evolutionary and functional conservation of WNT signaling molecules as well as human chromosomal localization, DAPPER1 and DAPPER2 genes are predicted to be potent cancer-associated genes.
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PMID:Identification and characterization of human DAPPER1 and DAPPER2 genes in silico. 1263 86

The catalog of gene alterations in human cancer grows rapidly. Gastric cancer is no exception and displays gene changes in multiple oncogenes, suppressor genes, and DNA repair genes. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell-cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. In addition, genetic instability is commonly seen. Gene amplification and protein overexpression of the growth factor receptors c-erbB2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. The clinical implications of some of the recent findings for diagnosis and therapy are discussed.
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PMID:Molecular mechanisms of carcinogenesis in gastric cancer. 1279 Mar 21

To determine the prevalence of gastric precancerous lesions and mucosal genetic alterations in relatives of a cluster of familial gastric cancer (FGC), we studied a kindred spanning two generations. The founder, daughter and niece underwent surgery for gastric cancer (GC); a son and other two daughters of the founder, presented with chronic dyspepsia. In all subjects, gastric mucosa samples were analysed for pathological features, Helicobacter pylori infection, microsatellite (MIN) and chromosomal (CIN) instability. The overexpression of mp53 and c-myc, and cytoplasmic beta-catenin delocalisation were found in the 2 younger cancer patients. All GC and gastritis patients had normal E-cadherin expression and were MIN-negative. Aneuploidy characterised all GC cases, and mixed euploid and aneuploid cell populations were present in the gastric biopsies from two of three 'at-risk' relatives. These two subjects, one of whom had severe active gastritis, and gastric mp53 and c-myc expression, were CagA-positive H. pylori-infected. DNA aneuploidy, p53 and c-myc expression disappeared after H. pylori eradication. In this FGC cluster, genetic abnormalities were found in first-degree relatives (3 patients) only in presence of H. pylori infection (2 cases H. pylori-positive versus 1 case H. pylori-negative) supporting the hypothesis that, besides the influence of a genetic profile, FGC may be, at least partly, mediated by intrafamilial clustering of H. pylori infection.
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PMID:Is there a link between environmental factors and a genetic predisposition to cancer? A lesson from a familial cluster of gastric cancers. 1285 70

E-cadherin germline missense mutations have been shown to be responsible for significant loss of protein activity. A new cytoplasmic E-cadherin germline missense mutation (V832 M) was recently identified in a hereditary diffuse gastric cancer (HDGC) Japanese family. This E-cadherin mutant was cloned in a Chinese hamster ovary cell model system and functionally characterized, in terms of aggregation and invasion. Cells expressing the germline V832M mutant fail to aggregate and invade into collagen, supporting the pathogenic role of this germline missense mutation in gastric cancer. We also tested the ability of this mutation to activate the TCF-LEF trascriptional activity, in comparison with three other E-cadherin missense mutations (T340A, A634V and A617T), associated to loss of E-cadherin function. All the E-cadherin mutants reduced TCF-LEF activation to a similar extent as the wild-type protein, suggesting that the oncogenic effect of the E-cadherin mutants is unlikely to be transmitted through a beta-catenin-dependent activation of the WNT pathway.
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PMID:The intracellular E-cadherin germline mutation V832 M lacks the ability to mediate cell-cell adhesion and to suppress invasion. 1294 22

Several tumor suppressor genes are located within human chromosome 11q23 region. We have cloned and characterized MFRP and RNF26 genes at 11q23.3. We also identified and characterized KIAA1735/MTHDIX gene at 11q23.1 and CLDN24 gene at 11q23.2 by using bioinformatics. Here, a novel human gene corresponding to a 5'-truncated FLJ20535 cDNA was identified. FLJ20535 corresponded to nucleotide position 55-2255 of FLJ13859, and nucleotide position 52-2169 of FLJ13859 was the coding region. Because of tetratricopeptide repeat (TPR) and armadillo repeat (ARM) domains within its gene product, the novel human gene was designated TPARM. Mouse E330017O07Rik cDNA was derived from mouse Tparm gene. Human TPARM (705 aa) and mouse Tparm (704 aa), showing 75.4% total-amino-acid identity, consist of TPR domain and three ARM domains. TPR domain of TPARM was most homologous to that of SMAP1, while ARM1-ARM3 domains of TPARM were most homologous to ARM7-ARM9 domains of CTNNB1 (also known as beta-catenin). TPARM might be implicated in the WNT-beta-catenin signaling pathway. TPARM mRNA was expressed in testis, prostate, lung, germinal center B-cells, and also in neuroblastoma, teratocarcinoma, colon cancer, and gastric cancer. Human TPARM gene was found to consist of 22 exons. TPARM gene, located between NCAM1 and DRD2 genes, was mapped to human chromosome 11q23.2. TPARM as well as NCAM1 and DRD2 were predicted to be candidate tumor suppressor genes within the commonly deleted region of malignant melanoma on 11q23.1-q23.2 (between microsatellite markers D11S1347 and D11S4122).
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PMID:Identification and characterization of TPARM gene in silico. 1296 6

The aims of this study were (1) to compare protein expression of adenomatous polyposis coli (APC) gene, beta-catenin, and E-cadherin between proximal and distal gastric adenocarcinomas and (2) to investigate their use as markers of cancer risk in intestinal metaplasia (IM). The epidemiology of proximal (cardia and gastroesophageal junction) and distal (antrum and corpus) gastric carcinomas is strikingly different despite similar morphologies. Carcinoma of the distal stomach is decreasing in incidence, whereas proximal carcinomas are increasing in incidence more than any other cancer in the Western world. This phenomenon has so far not been satisfactorily explained. IM is a well-established precursor for adenocarcinoma in the distal stomach but less so in the proximal stomach. However, its specificity as a predictor of gastric carcinoma is very low. Abnormalities of APC, beta-catenin, and E-cadherin are implicated in carcinogenesis of the stomach and may show aberrant expression at early stages of the neoplastic process. This study evaluated their immunoprofiles in 3 groups: biopsies showing normal mucosa (n = 108), biopsies showing IM (n = 99), and gastric cancer resections (n = 117). In the last group, carcinoma and noninvolved mucosa were studied. All groups included material from both proximal and distal locations. The results of this study showed that there were no differences between proximal and distal locations with regard to APC, beta-catenin, or E-cadherin expression. In both locations, high normal expression rates for all 3 molecules were present in biopsies showing normal gastric mucosa or IM and noninvolved mucosa from gastric cancer resections. In carcinomas, there was a significant decrease in both APC and E-cadherin expression, whereas beta-catenin showed abnormal cytoplasmic and nuclear staining. Diffuse-type cancers showed significantly lower E-cadherin expression than intestinal types. Noninvolved mucosa from cancer resections showed normal APC, beta-catenin, and E-cadherin expression regardless of adjacent tumor type and whether the mucosa was morphologically normal or showed IM. In conclusion, proximal and distal gastric carcinomas show no differences in expression of APC, beta-catenin, or E-cadherin; thus, the observed abnormalities do not seem to contribute to the observed epidemiologic differences between these tumors. Because loss of APC, decreased E-cadherin, or abnormal beta-catenin expression did not occur in IM, even when associated with carcinoma these immunostains are unlikely to be of value in the assessment of malignant potential in IM.
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PMID:Adenomatous polyposis coli gene, beta-catenin, and E-cadherin expression in proximal and distal gastric cancers and precursor lesions: an immunohistochemical study using tissue microarrays. 1296 49


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