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)

Aberrant promoter methylation is an important mechanism for gene silencing. Inflammation-related reactive oxygens contribute to this CpG island methylation. The nuclear factor-erythroid 2-related factor 2 gene (Nrf2) is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene and the CpG island methylation in non-cancerous gastric mucosa. The study was performed in 85 subjects (46 without gastric malignancies, non-GC group, and 39 with gastric cancer, GC group). The promoter methylation status of p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by methylation-specific-polymerase chain reaction. The Nrf2 gene genotypes were determined by the PCR-SSCP method. In the 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16, none for p21. The frequency of the methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95% CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was much higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95% CI, 1.26-8.59; p=0.015, and OR, 0.38; 95% CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95% CI, 1.14-7.36; p=0.026, and OR, 0.33; 95% CI, 0.13-0.88; p=0.027, respectively). Our results suggested that the promoter polymorphisms of Nrf2 gene may affect the methylation status of tumor-related genes, especially the p14 gene, under the influence of H. pylori-induced gastric inflammation.
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PMID:The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium. 1809 97

The development of multiple gastric cancer is a major problem after the endoscopic resection of the first early gastric cancer. To find out markers to identify high risk patients, we analyzed the microsatellite instability (MSI) status and hypermethylation of tumor-related genes in multiple gastric cancers. Sixty-four adenocarcinomas resected by endoscopy, including 32 early solitary gastric cancers (SGCs) from 32 patients and 32 multiple gastric cancers (MGCs) from 14 patients, were employed. We analyzed MSI and the methylation status of promoter regions of the hMLH1, MGMT, p16 and E-cadherin using methylation-specific Polymerase Chain Reaction. Expression levels of hMLH1 were examined by immunohistochemistry. MSI (+) was detected in 5 of the 14 (35.7%) patients with MGCs, and in only 3 of the 32 patients (9.3%) with SGCs. Significant differences were observed between the 2 groups (p<0.001). Hypermethylation of hMLH1 was more frequently detected in MGCs than in SGCs (p<0.01), whereas significant difference was not observed in the frequency of MGMT, p16 or E-cadherin promoter methylation between the 2 groups. In conclusion, our results indicate that inactivation of hMLH1 through promoter hypermethylation may be involved in the development of multiple gastric cancers following the MSI pathway.
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PMID:Genetic and epigenetic markers to identify high risk patients for multiple early gastric cancers after treatment with endoscopic mucosal resection. 1839 97

Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is the monoclonal growth of EBV-infected epithelial cells, and the entity was recognized only recently. EBV-associated GC is distributed worldwide and more than 90,000 patients are estimated to develop GC annually in association with EBV (10% of total GC). EBV-associated GC occurs in two forms in terms of the histological features, i.e., lymphoepithelioma-like GC and ordinary type of GC. Both share characteristic clinicopathological features, such as the preferential occurrence as multiple cancer and remnant stomach cancer. While the expression of EBV-latent genes is restricted to several in the infected cells (Latency I), EBV-associated GC shows gastric cell phenotype, resistance to apoptosis, and the production of immunomodulator molecules. Recently, global and non-random CpG island methylation of the promoter region of many cancer-related genes has been demonstrated with their decreased expression, such as p16 INK4A, p73 and E-cadherin. This abnormality is accompanied by methylation of the EBV genome itself, suggesting a process of virus-driven hypermethylation in the development of neoplastic cells. Further studies are necessary to determine the precise sequence of EBV infection, methylation, transformation and selection of the predominant clone within the stomach mucosa. Future studies are also desirable for the target and strategy of therapy, such as initiating viral replication or reversing the DNA methylation of cellular genes.
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PMID:Epstein-Barr virus and gastric carcinoma--viral carcinogenesis through epigenetic mechanisms. 1878 28

To investigate the relationship between p16 methylation and Helicobacter pylori infection in precancerous gastric lesions, a population-based study was conducted in Linqu County, a high-risk area of gastric cancer in China. Methylation status of p16 was evaluated by methylation-specific polymerase chain reaction in 920 subjects with precancerous gastric lesions. H. pylori status was determined by 13C-urea breath test and the density of H. pylori in biopsy specimens used for detecting methylation status was assessed by the modified Giemsa stain. The frequency of p16 methylation was significantly higher in subjects with H. pylori positive than those with H. pylori negative in each category of gastric lesion (p<0.001, respectively). Compared with H. pylori negative, the odds ratios (ORs) of p16 methylation were markedly elevated in subjects with H. pylori positive for superficial gastritis (OR, 9.45; 95% confidence interval [CI]: 2.94-30.41), chronic atrophic gastritis (OR, 15.92; 95%CI: 7.60-33.36), intestinal metaplasia (OR, 4.46; 95%CI: 2.44-8.13), indefinite dysplasia (OR, 3.67; 95%CI: 1.90-7.10), and dysplasia (OR, 2.48; 95%CI: 1.02-5.99). Moreover, the frequencies of p16 methylation increased steadily with the severity of H. pylori density in gastric mucosa. Compared with H. pylori negative, the OR of p16 methylation was 1.02-16.13 times higher in subjects with mild H. pylori infection, and 2.69-38.73 times higher in those with moderate/severe infection, respectively. Our findings indicate that p16 methylation was significantly associated with H. pylori infection in precancerous gastric lesions, suggesting that H. pylori infection could potently induce methylation of p16 CpG island.
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PMID:Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions: a population-based study. 1882 80

Replication-competent adenovirus (RCAd) constitutes an alternative in cancer therapy. For obtaining advanced RCAd generations with high oncolytic capability and a good safety profile, we constructed an E2F promoter-regulated RCAd carrying p16 gene, AdE2F-p16, in which the E1a gene was controlled by the E2F promoter. The experimental data showed that the E2F promoter endowed AdE2F-p16 with high specificity in cancer cells. While rarely replicating in normal cells, AdE2F-p16 could replicate in p16-deficient cancer cells, with 2,937- to 160,000-fold increased replicative capability in different cancer cell lines. AdE2F-p16 expressed p16 within cancer cells and led to potent antitumor efficacy in gastric cancer xenografts in nude mice, with a tumor inhibition rate of 59.14%. Due to the combined effects of cancer cell apoptosis induced by p16 expression and oncolysis by virus replication, the E2F promoter-regulated, p16-armed RCAd provides a promising strategy for cancer gene therapy.
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PMID:E2F promoter-regulated oncolytic adenovirus with p16 gene induces cell apoptosis and exerts antitumor effect on gastric cancer. 1903 63

The FoxM1 transcription factor, a master regulator of mitotic gene expression, promotes the pathogenesis of several malignancies. However, little is known about its expression and function in gastric cancer. In the present study we determined whether FoxM1 is over-expressed in gastric cancer, and whether it is required to maintain an immortal phenotype of gastric cancer cells. The over-expression of FoxM1 was observed in 37/42 tumour specimens from patients with gastric cancer. When FoxM1 in gastric cancer cells was knocked-down, impaired clonogenicity and cellular senescence occurred independently of p53 and p16 status. FoxM1 depletion led to the down-regulation of its target genes c-MYC and Skp2, coupled with the accumulation of the CDK inhibitor p27(kip1). Importantly, the FoxM1 inhibition-mediated cellular senescence and clonogenic defect was attenuated by the abolition of p27(kip1) induction. Telomerase reverse transcriptase, the key component of telomerase essential for cellular immortalization, was also inhibited in the FoxM1-depleted cells. Taken together, the FoxM1 gene is aberrantly activated in gastric cancer and its inhibition triggers p53- and p16-independent senescence of cancer cells by regulating the expression of p27(kip1) and other targets. These findings provide mechanistic insights into the role of FoxM1 in the pathogenesis of gastric cancer, which may have diagnostic and therapeutic implications in gastric cancer.
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PMID:FoxM1 is up-regulated in gastric cancer and its inhibition leads to cellular senescence, partially dependent on p27 kip1. 1923 38

RhoA, a member of the Rho GTPase family, has been extensively studied in the regulation of cytoskeletal dynamics, gene transcription, cell cycle progression, and cell transformation. Overexpression of RhoA is found in many malignancies and elevated RhoA activity is associated with proliferation phenotypes of cancer cells. We reported previously that RhoA was hyperactivated in gastric cancer tissues and suppression of RhoA activity could partially reverse the proliferation phenotype of gastric cancer cells, but the underlying mechanism has yet to be elucidated. It has been reported that RhoA activation is crucial for the cell cycle G(1)-S procession through the regulation of Cip/Kip family tumor suppressors in benign cell lines. In this study, we found that selective suppression of RhoA or its effectors mammalian Diaphanous 1 and Rho kinase (ROCK) by small interfering RNA and a pharmacologic inhibitor effectively inhibited proliferation and cell cycle G(1)-S transition in gastric cancer lines. Down-regulation of RhoA-mammalian Diaphanous 1 pathway, but not RhoA-ROCK pathway, caused an increase in the expression of p21(Waf1/Cip1) and p27(Kip1), which are coupled with reduced expression and activity of CDK2 and a cytoplasmic mislocalization of p27(Kip1). Suppression of RhoA-ROCK pathway, on the other hand, resulted in an accumulation of p15(INK4b), p16(INK4a), p18(INK4c), and p19(INK4d), leading to reduced expression and activities of CDK4 and CDK6. Thus, RhoA may use two distinct effector pathways in regulating the G(1)-S progression of gastric cancer cells.
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PMID:RhoA regulates G1-S progression of gastric cancer cells by modulation of multiple INK4 family tumor suppressors. 1937 85

Diffuse type gastric carcinoma is the most aggressive type of gastric cancer. This type of tumor is not preceded by precancerous changes and is associated with early-onset and hereditary syndromes. To test the hypothesis that DNA methylation profile would be useful for molecular classification of the diffuse type gastric carcinoma, DNA methylation patterns of the CpG Island of 17 genes were studied in 104 cases and 47 normal adjacent gastric mucosa by Methylation-specific PCR, Immunohistochemistry and Hierarchical clustering analysis. The most frequent methylated genes were FHIT, E-cadherin, BRCA1 and APC (>50%), followed by p14, p16, p15, p73, MGMT and SEMA3B (20-49%). Hierarchical clustering analysis reveals four groups with different clinical features. The first was characterized by hypermethylation of BRCA1 and younger age (<45 years old), and the second by hypermethylation of p14 and p16 genes, male predominance and Epstein-Barr virus infection. The third group was characterized by hypermethylation of FHIT and antrum located tumors and the fourth was not associated with any clinical variables. In normal adjacent mucosa only the p73 gene was significantly less methylated in comparison to tumor mucosa. DNA methylation identified subgroups of diffuse type gastric cancer. Hypermethylation of BRCA1 associated with young age suggests a role in early-onset gastric carcinoma.
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PMID:DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis. 1939 43

Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. To date, several reports on methylation of various genes in gastric cancer have been published. However, most of these studies have focused on cancer tissues or only a single gene. In this study, we determined the methylation frequency of 5 genes, including p16, Runx3, MGMT, DAPK, and RASSF1A, by methylation-specific polymerase chain reaction, in a series of formalin-fixed paraffin-embedded tissues including normal gastric mucosa (n = 20), intestinal metaplasia (n = 14), gastric epithelial dysplasia (n = 27), and early gastric adenocarcinoma (n = 16). Immunohistochemistry was used to determine expression of MGMT and RASSF1A protein. All 20 histologically normal gastric biopsy specimens were methylation-free for all 5 genes. Aberrant hypermethylation of RASSF1A was not detected in any case from intestinal metaplasia to early gastric adenocarcinoma. The methylation rate of the other 4 genes increased with the histological progression from intestinal metaplasia to gastric epithelial dysplasia, to early gastric adenocarcinoma. Methylation was detected in 28.6% of intestinal metaplasia (4/14), in 77.8% of gastric epithelial dysplasia (21/27), and in 87.5% of early gastric adenocarcinoma (14/16). The average number of methylated genes in intestinal metaplasia, gastric epithelial dysplasia, and early gastric adenocarcinoma was 0.43, 1.3, and 1.8, respectively. Concurrent methylation in 3 or more genes was found in 7.1% of intestinal metaplasia, 11.1% of gastric epithelial dysplasia, and 31.3% of early gastric adenocarcinoma. No correlation was found between hypermethylation and other clinicopathologic parameters such as age, sex, Helicobacter pylori infection, and location of lesions. However, we observed a significant association between hypermethylation of p16 and MGMT and elevated serum carcinoembryonic antigen level. No reduction or loss of RASSF1A expression was observed in our study. Weak or loss of MGMT expression was found in 20 lesions and was significantly associated with promoter hypermethylation (P < .01). Our results suggest that promoter hypermethylation of the p16, Runx3, MGMT, and DAPK genes may play an important role in the pathogenesis of gastric precancerous lesions and early gastric adenocarcinoma. Hypermethylation and inactivation of RASSF1A, however, could be a later event in malignant transformation. Further studies are warranted to determine whether the presence of promoter hypermethylation in gastric precancerous lesions is associated with higher risk of subsequent cancer development and how to interrupt the malignant transition from intestinal metaplasia and gastric epithelial dysplasia to early gastric adenocarcinoma by developing some gene-targeting therapies that may reverse aberrant methylation.
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PMID:Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions. 1969 81

In the course of gastric cancer development, gene silencing by DNA hypermethylation is an important mechanism. While DNA methylation often co-exists with histone modifications to regulate gene expression, the function of histone modifications in gene silencing in gastric cancer has not been evaluated in detail. p16, a well-known tumor suppressor gene, is frequently silenced in DNA hypermethylation manner in gastric cancer. Accordingly, we chose p16 to clarify whether there is a correlation among histone H3 lysine 9 (H3-K9) di-methylation, H3-K9 acetylation, DNA methylation and p16 expression in human gastric cancer. Three gastric cancer cells, MKN-45, SGC-7901 and BGC-823, were treated with 5-aza-2'-deoxycytidine (5-Aza-dC) and/or trichostatin A (TSA). We investigated p16 promoter DNA methylation status, p16 mRNA levels, regional and global levels of di-methyl-H3-K9 and acetyl-H3-K9 in four groups: i) 5-Aza-dC, ii) TSA, iii) the combination of 5-Aza-dC and TSA and iv) control group with no treatments. p16 silencing is characterized by DNA hypermethylation, H3-K9 hypoacetylation and H3-K9 hypermethylation at the promoter region. Treatment with TSA, increased H3-K9 acetylation at the hypermethylated promoter, but did not affect H3-K9 di-methylation or p16 expression. By contrast, treatment with 5-Aza-dC, reduced H3-K9 di-methylation, increased H3-K9 acetylation at the hypermethylated promoter and reactivated the expression of p16. Combined treatment restored the expression of p16 synergistically. In addition, 5-Aza-dC and the combined treatment did not result in global alteration of H3-K9 di-methylation. These results suggest that H3-K9 di-methylation, H3-K9 acetylation and DNA methylation work in combination to silence p16 in gastric cancer. The decreased H3-K9 di-methylation correlates with DNA demethylation and reactivation of p16. H3-K9 di-methylation as well as DNA methylation related to p16 silencing is limited to the promoter region. In addition to its effect on DNA methylation, 5-Aza-dC can act at histone modification levels to reactivate p16 expression in region-specific and DNA methylation-dependent manner.
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PMID:Promoter histone H3 lysine 9 di-methylation is associated with DNA methylation and aberrant expression of p16 in gastric cancer cells. 1978 43


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