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)

Trichostatin A (TSA) and S-adenosyl-L-homocysteine (AdoHcy) have been reported to affect histone modifications. To investigate the effects of two drugs that can reportedly affect chromatin remodeling, we analyzed the gene expression profiles of TSA and AdoHcy in a gastric cancer cell line using 14 K cDNA microarray. The significant analysis of microarray (SAM) identified 98 and 43 differentially expressed genes in TSA and AdoHcy treated sets, respectively, and selected genes were functionally classified. In the gastric cancer cell line, genes related to cell communication, cell growth/maintenance, and morphogenesis were highly expressed with TSA, and genes with cell growth/maintenance, metabolism, oxidoreductase activity were upregulated with AdoHcy. Genes downregulated with TSA included those controlling the cell cycle, cell growth/proliferation, DNA binding, and metabolism, whereas genes involved in calcium signaling, cell growth/proliferation, and metabolism were downregulated with AdoHcy. Furthermore, we identified the genes commonly expressed in both drug treatments. Compared to TSA, AdoHcy did not induce apoptosis in the SNU-16 gastric cancer cell line, and RT-PCR was performed for selective genes to confirm the microarray data. This gene expression profile analysis with TSA and AdoHcy should contribute to a greater understanding of the molecular mechanism of chromatin remodeling and cancer, and provide candidate genes for further studies involving the roles of histone modifications in gastric cancer.
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PMID:Gene expression analysis in human gastric cancer cell line treated with trichostatin A and S-adenosyl-L-homocysteine using cDNA microarray. 1546 84

Although acetylation-deacetylation of histones contributes to regulation of gene expression, few methods have been available to determine the whole-genome histone acetylation profile in specific cells or tissues. We have now developed a genome-wide screening method, differential chromatin scanning (DCS), to isolate genome fragments embedded in histones subject to differential acetylation. This DCS screening was applied to a human gastric cancer cell line incubated with or without an inhibitor of histone deacetylase (HDAC) activity, resulting in the rapid identification of more than 250 genome fragments. Interestingly, a number of cancer-related genes were revealed to be the targets of HDAC in the cancer cells, including those for tumour protein 73 and cell division cycle 34. Such differential acetylation of histone was also shown to be linked to the regulation of transcriptional activity of the corresponding genes. Among the isolated genome fragments, 94% (32/34) of them were confirmed to be bound to differentially acetylated histones, and the genes corresponding to 78% (7/9) of them exhibited differential transcriptional activity consistent with the level of histone acetylation. With its high fidelity, the DCS method should open a possibility to rapidly compare the genome-wide histone acetylation profiles and to provide novel insights into molecular carcinogenesis.
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PMID:High-throughput screening of genome fragments bound to differentially acetylated histones. 1556 49

SLC5A8 is a candidate tumour suppressor gene that is silenced in colon cancer, gastric cancer and possibly other cancers in humans. This gene codes for a transporter belonging to the Na(+)/glucose co-transporter gene family (SLC5). The cancer-associated silencing of the gene involves hypermethylation of CpG islands present in exon 1 of the gene. SLC5A8 is expressed in colon, ileum, kidney and thyroid gland. The protein coded by the gene mediates the Na(+)-coupled and electrogenic transport of a variety of monocarboxylates, including short-chain fatty acids, lactate and nicotinate. It may also transport iodide. The normal physiological function of this transporter in the intestinal tract and kidney is likely to facilitate the active absorption of short-chain fatty acids, lactate and nicotinate. One of the short-chain fatty acids that serves as a substrate for SLC5A8 is butyrate. This fatty acid is an inhibitor of histone deacetylases and is known to induce apoptosis in a variety of tumours including colonic tumour. Since butyrate is produced in the colonic lumen at high concentrations by bacterial fermentation of dietary fibre, we speculate that the ability of SLC5A8 to mediate the entry of this short-chain fatty acid into colonic epithelial cells underlies the potential tumour suppressor function of this transporter.
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PMID:Biological functions of SLC5A8, a candidate tumour suppressor. 1566 16

The caspases are a family of aspartic acid-specific proteases that fulfill varied and often critical roles in mammalian apoptosis or in the proteolytic activation of cytokines. Caspase-1 (interleukin-1beta-converting enzyme) is a member of the cysteine protease family, which cleaves target proteins following aspartic acid residues. We investigated caspase-1 expression in stomach cancer, tissues and cell lines. Of 301 consecutive gastric carcinomas, 58 cases (19.3%) showed the expressional loss of caspase-1. Loss of caspase-1 expression was significantly associated with pTNM stage (p=0.03), lymph node metastasis (p=0.01) and patient survival (p<0.01). Caspase-1 expression was also significantly correlated in an inverse manner with p53 expression (p<0.01). Among the 11 gastric cancer cell lines examined, three cell lines showed loss of expression at the protein and mRNA levels. On treatment with 5-aza-2'-deoxycytidine (5-aza-C), and/or trichostatin A (TSA), all three cell lines re-expressed caspase-1 mRNA. The above findings suggest that epigenetic events such as DNA methylation and histone deacetylation play important roles in the regulation of caspase-1, and that loss of caspase-1 expression is associated with poor survival in gastric carcinoma.
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PMID:Loss of caspase-1 gene expression in human gastric carcinomas and cell lines. 1580 17

Invasion and metastasis are critical determinants of cancer morbidity. Genes and molecules participating in these steps must be regarded as potential prognostic factors. Growth factors and their receptors, cell-cycle regulators, cell-adhesion molecules and matrix-degrading enzymes are those to be used as prognostic factors, including epidermal growth factor (EGF), EGF receptor, K-sam, HER-2, interleukin (IL)-8, vascular endothelial growth factor (VEGF), cyclin E, p27, E-cadherin, CD44v6, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). Alterations in epigenetics, such as aberrant DNA methylation and histone modification that are, in part, associated with the tumor progression of gastric cancer, can be candidate prognostic factors. The number of methylated genes may serve as a marker of tumor progression. Genetic polymorphism not only affects cancer susceptibility but also influences malignant phenotype; examples include single-nucleotide polymorphism in the HER-2 and MMP-9 genes. Comprehensive gene expression analyses are useful to search for novel genes related to invasion and metastasis and potential prognostic factors. Serial analysis of gene expression (SAGE) has identified several these genes, such as CDH17, APOE, FUS, COL1A1, COL1A2, GW112, and MIA. Overexpression of MIA is found to be associated with poor prognosis. Microarray analysis has great potential for identifying the characteristics of individual cancers, from the view point of gene expression profiles. A combination of these examinations can not only foretell a patient's prognosis but can also give information directly connected with personalized cancer medicine and prevention.
Gastric Cancer 2005
PMID:Molecular-pathological prognostic factors of gastric cancer: a review. 1586 15

Accumulated evidence has established that aberrant regulation of histone deacetylases (HDACs) is one of the major causes of the development of human malignancies. Among different iso-enzymes of HDAC and sirtuins grouped as the HDAC super family, little is known as to how histone deacetylase 2 (HDAC2) causes carcinogenesis in solid tumors. Here, in order to investigate the possible role of HDAC2 in gastric carcinogenesis, we analyzed the expression of HDAC2 in 71 gastric adenocarcinomas by immunohistochemistry. Moderate to strong expression of HDAC2 was found in 44 (62%) out of a total of 71 tumors. The majority of positive tumors, which were detected in the nucleus but not in normal gastric epithelium, did not express HDAC2 or showed only weak positive staining. Interestingly, we also noted that HDAC2 expression appeared to be associated with tumor aggressiveness as HDAC2 expression was observed to be statistically significant in advanced gastric cancer (P=0.0023, Chi-square test) and in positive lymph node metastasis (P=0.0713, Chi-square test). Taken together, these results suggest that HDAC2 may play an important role in the aggressiveness of gastric cancer.
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PMID:Increased expression of histone deacetylase 2 is found in human gastric cancer. 1586 7

Epigenetic alterations of the histone acetylation play an important role in the regulation of gene expression associated with cell cycles and apoptosis that may affect the chemosensitivity of gastric carcinomas. Recently, a histone deacetylase inhibitor, trichostatin A (TSA), was proven to be a chemo-sensitizer on human erythroleukemia cells. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of TSA on the chemosensitivity of several anticancer drugs in gastric carcinoma cells was investigated. Human gastric cancer cell lines, OCUM-8 and MKN-74, and 5 anticancer drugs, 5-fluorouracil (5-FU), paclitaxel (PTX), oxaliplatin (OXA), irinotecan (SN38) and gemcitabine (GEM) were used. In both gastric cancer cell lines, a synergistic anti-proliferative effect by the combination of TSA (30 ng/ml) with 5-FU, PTX or SN38 showed a synergistic anti-proliferative effect in OCUM-8 and MKN-74 cells. TSA increases the expression of p21, p53, DAPK-1 and the DAPK-2 gene in both OCUM-8 and MKN-74 cells. In conclusion, TSA is a promising chemotherapeutical agent in combination with anticancer drugs of 5-FU, PTX and SN38 in gastric cancer cell lines. The up-regulation of p53, p21, DAPK-1 and DAPK-2 might be associated with the synergistic effect of TSA.
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PMID:Histone deacetylase inhibitor, trichostatin A, increases the chemosensitivity of anticancer drugs in gastric cancer cell lines. 1686 56

Gastric carcinogenesis is a multistep process, during which numerous genetic and epigenetic alterations accumulate: there are abnormalities of growth factors/receptors, angiogenic factors, cell cycle regulators, DNA mismatch repair genes etc. These abnormalities define, at the same time, the biological character of the cancer cell and may thus serve as therapeutic targets. Genetic instability may cause accumulation of genetic abnormalities. The most important epigenetic alterations are DNA methylation, histone modification and chromatin remodeling. Some of these changes are common in gastric cancer, regardless of subtype, and some differ by histological type or (gastric or intestinal) mucin phenotype. Genetic polymorphism is a crucial endogenous cause and fundamental aspect of cancer risk. Importantly, genetic polymorphisms are also associated with the therapeutic efficacy and toxicity of anti-cancer drugs. Genomic science and technology such as Serial Analysis of Gene Expression (SAGE) allows the identification of novel genes and molecules specifically up-regulated or down-regulated in gastric cancer, e.g., RegIV and claudin-18 can be identified. Advances in our understanding of the genetic and molecular bases lead to improved diagnosis, personalised medicine and prevention of gastric cancer.
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PMID:Molecular pathobiology of gastric cancer. 1724 69

This study examined the relationship of protein kinase C (PKC) signaling with apoptosis induced by aspirin (ASA) in gastric surface cancer cells (AGS cell line). We found increased expression of two PKC isoforms (alpha and betaII) that translocated from the cytosol into the cell membrane fraction after ASA (40 mM) stimulation. PKC betaI expression markedly decreased in response to ASA treatment. This process was independent of caspase activation because no caspase inhibitors used (i.e., inhibitors to caspase 3, 6, 7, 8, and total caspase activity) significantly changed PKC processing, although inhibition of caspase cascade activity markedly attenuated the apoptosis induced by ASA as measured by DNA-histone complex formation. Upstream PKC signaling induced by ASA seems to play an important role in the regulation of apoptosis because PKC inhibitors significantly reduced the magnitude of DNA-histone complex formation. We conclude that ASA-induced apoptosis in gastric cancer cells is mediated, at least in part, through a PKC mechanism involving the (alpha) and (beta) isoforms and that PKC signaling operates upstream of the caspase cascade, which when activated elicits its downstream effects on DNA degradation.
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PMID:Aspirin-induced apoptosis in human gastric cancer epithelial cells: relationship with protein kinase C signaling. 1725 32

Epigenetic modifications of genomic DNA and histones alter the chromatin structure to regulate the accessibility of transcription factors to the promoter or enhancer regions. In 2003, we identified and characterized JMJD1C (TRIP8) consisting of TRI8H1 domain with C2HC4-type zinc finger-like motif, TRI8H2 domain with thyroid hormone receptor beta-binding region, and JmjC domain. JMJD1A (TSGA), JMJD1B (5qNCA) and JMJD1C with the common domain architecture are histone H3K9 demethylases implicated in the nuclear hormone receptor-based transcriptional regulation. Here, comparative integromics on JMJD1C gene is reported. JMJD1C variant 1, previously reported, consists of exons 1, 2 and 3-26, while JMJD1C variant 2 characterized in this study was transcribed from novel exon 1B located 5' to exon 3. Four human JMJD1C ESTs were transcribed from exon 1, while 14 human JMJD1C ESTs from exon 1B. All of 26 mouse Jmjd1c ESTs were transcribed from exon 1b. These facts indicate that JMJD1C variant 2 transcribed from exon 1B was the major transcript. Human JMJD1C variant 2 with TRI8H1, TRI8H2, and JmjC domains showed 85.7% total-amino-acid identity with mouse Jmjd1c. Human JMJD1C mRNA was expressed in undifferentiated embryonic stem (ES) cells, pancreatic islet, diffuse-type gastric cancer, and other tissues or tumors. Mouse Jmjd1c mRNA was expressed in fertilized egg, blastocyst, undifferentiated ES cells, embryonic germ cells, c-Kit+/Sca-1+/Lin- hematopoietic stem cells, pancreatic islet, and other tissues. Comparative genomics analyses revealed that binding sites for POU5F1 (OCT3/OCT4), AP-1, and bHLH transcription factors within the promoter region located 5' to exon 1B of human JMJD1C gene were conserved in chimpanzee, cow, mouse and rat JMJD1C orthologs. POU5F1-mediated expression of JMJD1C histone demethylase is implicated in the reactivation of silenced genes in undifferentiated ES cells, pancreatic islet, and diffuse-type gastric cancer.
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PMID:Comparative integromics on JMJD1C gene encoding histone demethylase: conserved POU5F1 binding site elucidating mechanism of JMJD1C expression in undifferentiated ES cells and diffuse-type gastric cancer. 1754 25


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