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)

WNT signaling pathway plays a key role in carcinogenesis and embryogenesis. We have cloned and characterized the human WNT5B. Overlapping WNT5B cDNAs, containing 1080-bp ORF, were isolated. WNT5B encoded a 359-amino-acid polypeptide with the N-terminal signal peptide, four N-linked glycosylation sites, and consensus amino-acid residues conserved among the WNT family. WNT5B showed 80.5% total-amino-acid identity with WNT5A. Comparison between nucleotide sequence of WNT5B cDNA and human genome draft sequences revealed that the WNT5B gene, consisting of 4 exons, was located on human chromosome 12p13.3 region. Northern blot analyses with W5B2 probe detected the 2.8- and 2.4-kb WNT5B mRNAs. WNT5B was moderately expressed in adult prostate and fetal brain, and weakly expressed in fetal lung, kidney, adult liver, ovary, and small intestine. Among human cancer cell lines, WNT5B was expressed in gastric cancer cell lines MKN7, MKN45, KATO-III, and a teratocarcinoma cell line NT2. WNT5B might be implicated in human carcinogenesis through activation of the WNT-beta-catenin-TCF signaling pathway, just like Wnt5a.
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PMID:Molecular cloning and characterization of human WNT5B on chromosome 12p13.3 region. 1144 50

WNT signaling pathway is implicated in carcinogenesis and embryogenesis. We have previously cloned and characterized WNT10A and WNT6, which are clustered in human chromosome 2q35 region. In this study, we investigated expression of WNT10A and WNT6 in gastric cancer. The 3.0- and 2.4-kb WNT10A mRNAs were expressed in gastric cancer cell lines MKN7, MKN45 and MKN74. The 2.0-kb WNT6 mRNA was expressed in gastric cancer cell lines MKN28 and MKN74. WNT10A was up-regulated in 3 out of 6 cases of primary gastric cancer, while WNT6 was not up-regulated in primary gastric cancer. Effects of inflammatory cytokines and Helicobacter pylori (H. pylori) on expression of WNT10A and WNT6 were next investigated. Interferon gamma (IFNgamma) failed to induce up-regulation of WNT10A and WNT6. Tumor necrosis factor alpha (TNFalpha) induced up-regulation of WNT10A in MKN45 cells. Up-regulation of WNT10A reached maximum at 6 h after TNFalpha treatment. H. pylori also induced up-regulation of WNT10A in MKN45 cells. These results strongly suggest that up-regulation of WNT10A induced by TNFalpha and H. pylori might play key roles in human gastric cancer through activation of WNT--beta-catenin--TCF signaling pathway.
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PMID:Up-regulation of WNT10A by tumor necrosis factor alpha and Helicobacter pylori in gastric cancer. 1149 32

Disruption of the APC/beta-catenin/Tcf pathway has been proposed as an important step in the development of cancer. The Tcf-4 transcription factor gene was reported to be one of the targets of microsatellite instability (MSI) in colorectal cancers in with MSI. We carried out a sequencing analysis of the Tcf-4 gene in 41 Japanese patients with gastrointestinal tumors with MSI as well as in cancer cell lines. Three of 21 (14.3%) colorectal tumors with MSI contained a mutant Tcf-4 gene encoding 1-bp deletion in an (A)9 repeat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mutations were detected in 20 gastric tumors with MSI, or in gastric cancer cell lines. Additionally, we found a novel transcript of the Tcf-4 gene which contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 coding sequence. Sequencing analysis revealed that the inserted fragment was 60% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted in truncation of Tcf-4, similar to the 1-bp deletion in the (A)9 repeat. Therefore, in part of the Japanese colorectal tumors with MSI, frameshift mutations in Tcf-4 may be of functional significance. Functional alterations in the Tcf-4 signaling network in gastrointestinal tumorigenesis require further investigations.
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PMID:Genetic alterations in the human Tcf-4 gene in Japanese patients with sporadic gastrointestinal cancers with microsatellite instability. 1152 55

Mouse Nkd is a Dishevelled-binding protein, functioning as a negative regulator of WNT - beta-catenin - TCF signaling pathway. Here, human NKD1 and NKD2 were cloned and characterized. NKD1 and NKD2 were predicted to encode 470- and 451-amino-acid polypeptide, respectively. NKD1 and NKD2, showing 43.8% total amino-acid identity, were more homologous in the NH1, NH2, NH3, and NH4 domains. The NH2 domain of NKD1 and NKD2 contained the EF-hand motif. Exon-intron structures of NKD1 and NKD2 genes, consisting of 10 exons, were well conserved. NKD1 was highly expressed in fetal kidney, while NKD2 was moderately expressed in fetal kidney, lung, and adult lung. NKD1 was up-regulated in colorectal cancer cell line SW480, gastric cancer cell line TMK1, and pancreatic cancer cell line Hs700T. NKD2 was up-regulated in gastric cancer cell line MKN45, pancreatic cancer cell line BxPC-3, and esophageal cancer cell lines TE6, and TE13. NKD1 and NKD2 were up-regulated together in 1 case of primary gastric cancer out of 10 cases, and were down-regulated together in 2 cases. Up-regulation of NKD1 or NKD2 might be due to a negative feed-back mechanism. Alternatively, genetic alteration of NKD1 or NKD2 might lead to activation of the WNT - beta-catenin - TCF signaling pathway.
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PMID:Molecular cloning, gene structure, and expression analyses of NKD1 and NKD2. 1160 95

Mouse Wnt-3 is a proto-oncogene, which is activated by mouse mammary tumor virus (MMTV). Human WNT3 cDNA fragment, previously isolated by another group, corresponds to a partial coding sequence. WNT3 cDNA, spanning the complete coding sequence, was isolated in this study. WNT3 encoded 355-amino-acid polypeptide with the N-terminal signal peptide and two N-linked glycosylation sites. WNT3 was most homologous to WNT3A (84.2% total amino-acid identity) among human WNTs. The WNT3 gene on the human chromosome 17q21 region consisted of five exons. WNT3 mRNAs were detected in fetal brain, adult brain, and testis by Northern blot analyses. WNT3 mRNA was relatively highly expressed in A549 cells (lung cancer) and MKN45 cells (gastric cancer) among 37 human cancer cell lines. WNT3 was significantly up-regulated in a case of primary breast cancer and in a case of primary rectal cancer among various types of human primary cancers. These results strongly suggest that WNT3 might play a key role in some cases of human breast, rectal, lung, and gastric cancer through activation of the WNT - beta-catenin - TCF signaling pathway, similar to mouse Wnt-3.
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PMID:Molecular cloning and characterization of human WNT3. 1160 97

WNT2 is one of proto-oncogenes with the potential to activate the WNT - beta-catenin - TCF signaling pathway, which is most homologous to WNT2B among members of the human WNT gene family. Here, expression of WNT2 mRNA was comprehensively investigated. WNT2 mRNAs were highly expressed in fetal lung, and weakly expressed in placenta. Among 2.0-, 2.9-, 4.1-, and 6.0-kb WNT2 mRNAs, the 2.0-kb WNT2 mRNA was the major transcript in fetal lung. In 3 cases of prostate cancer and 1 case each of lung cancer and cervical cancer, WNT2 was over-expressed in non-cancerous portion as well as in primary tumor. WNT2 was up-regulated in 14 out of 18 cases of primary colorectal cancer, 4 out of 7 cases of uterus tumor, 2 out of 9 cases of breast cancer, and in 2 out of 14 cases of kidney tumor. Up-regulation of WNT2 was also detected in 4 out of 8 cases of primary gastric cancer by using expression array filter hybridization, and in 10 out of another 10 cases of primary gastric cancer by using cDNA-PCR. Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer might play a key role in carcinogenesis through activation of the WNT - beta-catenin - TCF signaling pathway.
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PMID:Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. 1160 1

Gastric cancers are commonly subdivided into intestinal and diffuse subtypes on a morphologic basis, supported by corollary evidence of differences at the pathogenetic and molecular levels. Chronic atrophic gastritis with intestinal metaplasia is a common precursor lesion for the intestinal type of carcinoma. To identify early molecular changes, in this study we have examined 13 surgical specimens both for the expression of E-cadherin, p53 and beta-catenin by immunohistochemistry and for methylation of the CDH1 promoter (E-cadherin) by bisulfite genomic sequencing of laser capture microdissected samples. Each specimen examined contained areas of normal (nonmetaplastic) gastric mucosa, as well as areas of intestinal metaplasia and/or carcinoma. Reduced or absent E-cadherin and partial to complete methylation of one to multiple CpG sites examined in the CDH1 promoter were observed in all of the metaplasia samples. Thus, the methylation status of the CDH1 promoter and expression of E-cadherin together provide strong evidence that loss of E-cadherin is an early event in intestinal type gastric carcinogenesis. In contrast, expression of p53, assumed to be mutant p53, was generally not detected (except for isolated cells) until the carcinoma stage in tissues from these patients. These results suggest that mutation of p53 is a late event in intestinal type gastric cancer. The level of beta-catenin expression did not appear to change between normal, metaplastic and carcinoma cells of intestinal type, and no nuclear staining was visible in any of the tissues. These results suggest that the Wnt signaling pathway is not upregulated in this type of cancer.
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PMID:Loss of E-cadherin expression in gastric intestinal metaplasia and later stage p53 altered expression in gastric carcinogenesis. 1166 47

ICAT inhibits the interaction between beta-catenin and TCF transcription factors. As ICAT might be a tumor suppressor gene with the potential to negatively regulate the WNT - beta-catenin - TCF signaling pathway, ICAT related gene in the human genome draft sequence was searched for. Here, the LZIC gene, a novel gene encoding a 190-amino-acid polypeptide with leucine zipper domain and ICAT homologous domain, was cloned and characterized. Amino-acid identity between LZIC and ICAT in the ICAT homologous domain was 38%. The LZIC gene, consisting of at least 8 exons, was located in the human chromosome 1p36.32-pter region. The major 5.2-kb LZIC mRNA and minor 2.1-, 1.6-, and 1.0-kb LZIC mRNAs were expressed almost ubiquitously in normal human tissues. LZIC was expressed in all cancer cell lines examined in this study, and was significantly up-regulated in a gastric cancer cell line MKN74 and 5 cases of primary gastric cancer. As LZIC contains ICAT homologous domain, LZIC might inhibit the interaction between beta-catenin and TCF transcription factors, just like ICAT, and, up-regulation of LZIC in gastric cancer might be due to a negative feed-back mechanism to inhibit the WNT - beta-catenin - TCF signaling pathway.
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PMID:Molecular cloning and characterization of LZIC, a novel gene encoding ICAT homologous protein with leucine zipper domain. 1171 74

WNT2 is one of proto-oncogenes to activate the beta-catenin - TCF signaling pathway. WNT2B is a paralogue of WNT2, which encodes WNT2B1 and WNT2B2 isoforms due to alternative splicing using alternative promoter. Here, regulation of WNT2, WNT2B1, and WNT2B2 mRNAs in MCF-7 cells (breast cancer), NT2 cells (teratocarcinoma), and MKN45 cells (gastric cancer) were investigated. WNT2B2, but not WNT2 and WNT2B1, was expressed in MCF-7 cells. beta-estradiol (100 nM) induced a transient up-regulation of WNT2 in MCF-7 cells, and also induced down-regulation of WNT2B2. WNT2B2, but not WNT2B1, was expressed in NT2 cells, and WNT2 was slightly expressed in NT2 cells. Retinoic acid (10 microM) induced a transient up-regulation of WNT2 in NT2 cells. WNT2B2, but not WNT2 and WNT2B1, was slightly expressed MKN45 cells, and tumor necrosis factor alpha did not affect expression of WNT2, WNT2B1, and WNT2B2 mRNAs in MKN45 cells. This is the first report on differential regulation of WNT2, WNT2B1, and WNT2B2 mRNAs in human cancer cell lines. Up-regulation of WNT2 mRNA by estrogen might play a key role in some cases of human breast cancer through activation of the beta-catenin - TCF signaling pathway.
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PMID:Differential regulation of WNT2 and WNT2B expression in human cancer. 1171 82

WNT10A and WNT10B genes are human orthologues of mouse proto-oncogene Wnt-10b. We have previously cloned and characterized WNT10A, and demonstrated up-regulation of WNT10A by tumor necrosis factor alpha (TNFalpha) in gastric cancer. Here, we cloned and characterized human WNT10B, which showed Gly60Asp amino-acid substitution compared with human WNT10B previously reported by another group. Gly60 WNT10B allele was identified in 2 human genome draft sequences and 7 human ESTs, while Asp60 WNT10B allele was not identified in any human genome draft sequences or ESTs. The Gly60-type WNT10B cDNA isolated in this study might be derived from more common WNT10B allele. WNT10B was most homologous to WNT10A (64.5% total amino-acid identity) among human WNTs. Variable region in the WNT core domain of WNT10B and WNT10A were longer than that of other WNTs, such as WNT2B1, WNT2B2, WNT3, WNT3A, WNT5B, WNT7B, WNT8A, WNT11, WNT14, and WNT14B/WNT15. We next investigated expression of WNT10B in human gastric cancer. WNT10B was moderately expressed in MKN45 and MKN74 cells, and weakly expressed in Okajima, TMK1, MKN7, MKN28, and KATO-III cells. Because interferon gamma (IFNgamma) and TNFalpha were frequently elevated in gastric mucosa with Helicobacter pylori infection, effects of IFNgamma and TNFalpha on WNT10B expression in MKN45 cells were investigated. TNFalpha induced transient up-regulation of WNT10B mRNA in MKN45 cells. Up-regulation of WNT10B in human gastric mucosa might lead to gastric carcinogenesis through activation of the beta-catenin - TCF signaling pathway, just like up-regulation of Wnt-10b in mouse mammary gland leads to mammary carcinogenesis.
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PMID:Proto-oncogene WNT10B is up-regulated by tumor necrosis factor alpha in human gastric cancer cell line MKN45. 1171 88


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