Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kermit is a Xenopus orthologue of human GIPC1/GIPC, which interacts with Frizzled-3 (FZD3) class of WNT receptor to modulate WNT signaling. GIPC1 interacts with TGFbeta type III receptor to enhance TGFbeta signaling. We have recently cloned and characterized a novel GIPC1-related gene, GIPC2. During isolation of GIPC2, we identified another novel GIPC1-related gene, GIPC3, by using bioinformatics. In this study, we isolated GIPC3 cDNAs from poly(A)+ RNA of human fetal lung. GIPC3 encoded a 312-amino-acid protein with a central PDZ domain, which showed 59.9% total-amino-acid identity with GIPC1, 55.3% total-amino-acid identity with GIPC2, and 57.2% total-amino-acid identity with Xenopus Kermit. GIPC3 gene on human chromosome 19p13.3 was found to consist of 6 exons, just like GIPC1 gene and GIPC2 gene. The 4.5-kb GIPC3 mRNA was almost ubiquitously expressed in normal adult tissues as well as in normal fetal tissues. Expression level of GIPC3 mRNA was relatively higher in jejunum, followed by lymph node, parietal lobe in brain, fetal spleen, and fetal thymus. GIPC3 mRNA was expressed in cervical cancer cell line HeLa S3, chronic myelogenous leukemia cell line K-562, and melanoma cell line G-361. GIPC3 mRNA was also expressed in gastric cancer cell lines TMK1 and MKN7; however, expression level of GIPC3 mRNA in TMK1 and MKN7 cells were significantly lower than that in normal stomach. This is the first report on molecular cloning of GIPC3, the third member of the GIPC gene family.
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PMID:Molecular cloning and characterization of human GIPC3, a novel gene homologous to human GIPC1 and GIPC2. 1183 71

The PTEN/MMAC1/TEP1 gene (phosphatase and tensin homolog deleted on chromosome 10/mutated in multiple advanced cancers/TGF-beta regulated and epithelial cell enriched phosphatase 1), which regulates the signaling pathways of Akt, is a novel tumor suppressor gene implicated in multiple cancers. Because a number of tumor suppressor genes are known to be silenced by aberrant promoter methylation, we examined the methylation status of the 5' CpG islands of PTEN using methylation-specific PCR. The altered expression of PTEN in 310 gastric carcinomas was analyzed by immunohistochemical staining using tissue-array and clinicopathologic profiles related to PTEN expression were characterized. Of 310 consecutive gastric carcinomas, 62 cases (20%) showed expression loss of PTEN. Altered PTEN expression was significantly associated with tumor depth and size, lymphatic invasion, advanced stage, pTNM stage, and patient survival (p < 0.001). The promoter methylation frequency of PTEN was found to be present in 26 (39%) of 66 cases examined, and 19 (73%) of 26 gastric cancer tissues showing promoter methylation exhibited the loss of PTEN expression. Abnormalities in the expression of PTEN significantly correlated with promoter methylation (p < 0.001). In conclusion, silencing of the PTEN gene occurs frequently in gastric carcinoma and aberrant promoter methylation is a major mechanism of silencing of the PTEN gene. The abnormalities of the PTEN gene are associated with tumor progression, metastasis, and survival.
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PMID:Promoter methylation and silencing of PTEN in gastric carcinoma. 1189 7

Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells. Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and a mutation (R122C) occurring within the conserved Runt domain abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.
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PMID:Causal relationship between the loss of RUNX3 expression and gastric cancer. 1247 50

GIPC1/RGS19IP1/GIPC, GIPC2, and GIPC3 are a family of central PDZ-domain proteins with GH1 and GH2 domains. GIPC1 interacts with GTPase-activating protein RGS19/RGS-GAIP, TGFbeta type III receptor, receptor tyrosine kinase TrkA, and integrin alpha6A subunit. Xenopus homologue of human GIPCs interacts with Frizzled-3 class of WNT receptor. We investigated expression of human GIPC1 mRNA in normal tissues, cancer cell lines, and primary tumors. GIP1A probe (nucleotide position 1075-1483 of GIPC1 cDNA) hybridized to GIPC1 mRNA of 1.8 kb in size. GIPC1 mRNA was almost ubiquitously expressed in various normal tissues. Expression level of GIPC1 mRNA was relatively lower in bone marrow and peripheral blood leukocytes. GIPC1 mRNA was relatively highly expressed in gastric cancer cell lines OKAJIMA, TMK1, MKN28, MKN45, MKN74, KATO-III, pancreatic cancer cell line AsPC-1, colorectal cancer cell line SW480, and lung cancer cell line A549. On the other hand, GIPC1 mRNA was almost undetectable in leukemia/lymphoma cell lines HL-60, Raji, and Daudi. Expression of GIPC1 mRNA was down-regulated in 12 out of 14 cases of primary kidney tumors, 10 out of 18 cases of primary colorectal tumors, 3 out of 8 cases of primary gastric cancer, 3 out of 3 cases of primary prostate cancer. Because GIPC1 induces increased expression of TGFbeta type III receptor at the cell surface and enhanced responsiveness to TGFbeta, down-regulation of GIPC1 mRNA in tumors might promote cellular proliferation through interference of TGFbeta signaling.
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PMID:Expression of human GIPC1 in normal tissues, cancer cell lines, and primary tumors. 1195 58

GIPC1/GIPC/RGS19IP1, GIPC2, and GIPC3 genes constitute the human GIPC gene family. GIPC1 and GIPC2 show 62.0% total-amino-acid identity. GIPC1 and GIPC3 show 59.9% total-amino-acid identity. GIPC2 and GIPC3 show 55.3% total-amino-acid identity. GIPCs are proteins with central PDZ domain and GIPC homology (GH1 and GH2) domains. PDZ, GH1, and GH2 domains are conserved among human GIPCs, Xenopus GIPC/Kermit, and Drosophila GIPC/ LP09416. Bioinformatics revealed that GIPC genes are linked to prostanoid receptor genes and DNAJB genes in the human genome as follows: GIPC1 gene is linked to prostaglandin E receptor 1 (PTGER1) gene and DNAJB1 gene in human chromosome 19p13.2-p13.1 region; GIPC2 gene to prostaglandin F receptor (PTGFR) gene and DNAJB4 gene in human chromosome 1p31.1-p22.3 region; GIPC3 gene to thromboxane A2 receptor (TBXA2R) gene in human chromosome 19p13.3 region. GIPC1 and GIPC2 mRNAs are expressed together in OKAJIMA, TMK1, MKN45 and KATO-III cells derived from diffuse-type of gastric cancer, and are up-regulated in several cases of primary gastric cancer. PDZ domain of GIPC family proteins interact with Frizzled-3 (FZD3) class of WNT receptor, insulin-like growth factor-I (IGF1) receptor, receptor tyrosine kinase TrkA, TGF-beta type III receptor (TGF-beta RIII), integrin alpha6A subunit, transmembrane glycoprotein 5T4, and RGS19/RGS-GAIP. Because RGS19 is a member of the RGS family that regulate heterotrimeric G-protein signaling, GIPCs might be scaffold proteins linking heterotrimeric G-proteins to seven-transmembrane-type WNT receptor or to receptor tyrosine kinases. Therefore, GIPC1, GIPC2 and GIPC3 might play key roles in carcinogenesis and embryogenesis through modulation of growth factor signaling and cell adhesion.
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PMID:GIPC gene family (Review). 1201 74

GIPC1/GIPC, GIPC2, and GIPC3 are a family of central PDZ-domain proteins. GIPC1/GIPC interacts with TGFbeta type III receptor, receptor tyrosine kinase TrkA, integrin alpha6A subunit, and GTPase-activating protein RGS-GAIP, while Xenopus homologue of human GIPCs interacts with Frizzled-3 (FZD3) class of WNT receptor. Here, we investigated expression of GIPC2 mRNA in human gastric, pancreatic, and breast cancer cell lines. GIPC2 mRNA was relatively highly expressed in OKAJIMA, TMK1, MKN45, and KATO-III cells derived from diffuse type of gastric cancer, but was almost undetectable in MKN7, MKN28, and MKN74 cells derived from intestinal type of gastric cancer as well as in other cell lines derived from pancreatic and breast cancer. Tumor necrosis factor alpha and interferon gamma, which are elevated in gastric mucosa with Helicobacter pylori infection, did not affect the expression level of GIPC2 mRNA in MKN45 cells. Up-regulation of GIPC2 mRNA was detected in 7 out of 10 cases of primary gastric cancer by using cDNA-PCR, and in 4 out of another 8 cases of primary gastric cancer by using expression array filter hybridization. GIPC2 might play important roles in human gastric cancer through modulation of growth factor signaling or cell adhesion.
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PMID:Up-regulation of GIPC2 in human gastric cancer. 1201 97

Transforming growth factor beta type II receptor (TGFbeta-IIR) has been found to be altered in primary gastrointestinal carcinomas. So far relatively few facts are known about the expression of TGFbeta-IIR in primary gastric cancer. Therefore, in the present study, TGFbeta-IIR expression was analyzed in 130 primary gastric carcinomas and correlated with clinicopathological findings, the presence of a mutator phenotype, the mutational status of the TGFbeta-IIR polyadenine tract and survival. TGFbeta-IIR expression was analyzed immunohistochemically. Microsatellite instability was evaluated using a PCR-based assay and the polyadenine run inside the TGFbeta-IIR gene was sequenced. A complete loss of TGFbeta-IIR expression could be found in 55 (42.3%) of these carcinomas. Loss of TGFbeta-IIR expression was significantly correlated with diffuse-type carcinomas according to the Lauren classification as well as with signet ring cell carcinomas and a lower grade of differentiation. No correlation was found with the overall prognosis, the presence of a mutator phenotype, or a mutated TGFbeta-IIR. Thus, our data suggest the existence of a further definite subgroup of diffuse-type gastric carcinomas with altered TGFbeta-IIR expression, independent from a mutator phenotype with TGFbeta-IIR gene mutations. However, according to our results, in gastric cancer neither loss of TGFbeta-IIR expression nor mutations of the TGFbeta-IIR are of prognostic value.
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PMID:Transforming growth factor beta type II receptor expression in gastric cancer: evidence for two independent subgroups. 1217 10

The Runt domain transcription factors, RUNX1, RUNX2 and RUNX3, are integral components of signaling cascades mediated by both TGF-beta and bone morphogenetic proteins (BMPs) in several important biological systems. RUNX2 functions synergistically with Smad1 and Smad5 to regulate bone-specific genes when BMP induces osteogenesis. RUNX3, which has been mapped to locus 1p36, is a major tumor suppressor of gastric cancer and appears to be an important component of the TGF-beta-induced tumor suppressor pathway. A possible relationship between the TGF-beta-induced tumor-suppressor pathway and a postulated tumor suppressor gene on 1p36 must be examined.
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PMID:RUNX transcription factors as key targets of TGF-beta superfamily signaling. 1257 34

Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders.
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PMID:Molecular dimensions of gastrointestinal tumors: some thoughts for digestion. 1451 68

Experimental infection with Helicobacter pylori in Mongolian gerbils results in chronic gastritis and gastric cancer. To investigate epithelial cell proliferation, apoptosis, and mucosal cytokine responses in gastritis, Mongolian gerbils were infected with the H pylori SS1 strain. At 4 weeks post-infection, gastritis was predominantly within the antrum, but extended to the corpus in approximately 50% of gerbils by 36 weeks. Epithelial cell proliferation and apoptosis in glandular epithelial cells were increased with infection. Antral cell proliferation, but not apoptosis, correlated significantly with gastric inflammation. In female gerbils, H pylori significantly increased expression of transcripts for IFN-gamma and IL-12p40, but not TGF-beta or IL-10, in the gastric mucosa. Significantly reduced IFN-gamma and IL-12p40 responses were observed in male gerbils infected with H pylori, but epithelial proliferative and apoptotic responses were comparable to those of females. These studies demonstrate that the female gerbil cytokine response to H pylori has a Th1 profile and that there are gender differences in the magnitude of the gastric cytokine responses to H pylori. The absence of a down-regulatory cytokine response may account for the more severe gastritis observed with H pylori infection in gerbils than in mice.
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PMID:Gastric mucosal cytokine and epithelial cell responses to Helicobacter pylori infection in Mongolian gerbils. 1474 2


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