[Gene expression profiling in stomach cancer and its clinical application].
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Gene Expression Profiling↗
Biomedical subjects
Wataru Yasui
Publications and source records attributed to Wataru Yasui.
Loss of heterozygosity and histone hypoacetylation of the PINX1 gene are associated with reduced expression in gastric carcinoma.
The expression of PINX1, a possible telomerase inhibitor and a putative tumor suppressor, has not been studied in human cancers, including gastric cancer (GC). We examined expression of PINX1 by quantitative reverse transcription (RT)-PCR in 73 cases of GC, and 45 of these cases were further studied for loss of heterozygosity (LOH) by PCR with microsatellite marker D8S277. Reduced expression (tumor vs normal ratio<0.5) of PINX1 was detected in 50 (68.5%) of 73 cases of GC. GC tissues with reduced expression of PINX1 showed significantly higher telomerase activities as measured by telomeric repeat amplification protocol than those with normal expression of PINX1 (P=0.031). LOH of PINX1 locus was detected in 15 (33.3%) of 45 cases of GC and was correlated significantly with reduced expression of PINX1 (P=0.031). Expression of PINX1 in a GC cell line, MKN-74, was induced by treatment with trichostatin A (TSA) or nicotinamide (NAM). Chromatin immunoprecipitation assay of MKN-74 cells revealed that acetylation of histone H4 in the 5' untranslated region (UTR) of PINX1 was enhanced by treatment with TSA or NAM, whereas acetylation of histone H3 was not changed by TSA or NAM. In addition, TSA or NAM treatment led to inhibition of telomerase activity in MKN-74 cells. These results indicate that LOH of PINX1 locus and hypoacetylation of histone H4 in the 5' UTR of PINX1 are associated with reduced expression of PINX1 in GC.
Acetylation↗
Histone H3 acetylation is associated with reduced p21(WAF1/CIP1) expression by gastric carcinoma.
Histone acetylation appears to play an important role in transcriptional regulation. Inactivation of chromatin by histone deacetylation is involved in the transcriptional repression of several tumour suppressor genes, including p21(WAF1/CIP1). However, the in vivo status of histone acetylation in human cancers, including gastric carcinoma, is not well understood. This study shows that histone H3 in the p21(WAF1/CIP1) promoter region is hypoacetylated and that this hypoacetylation is associated with reduced p21(WAF1/CIP1) expression in gastric carcinoma specimens. Chromatin immunoprecipitation assays revealed that histone H3 was hypoacetylated in the p21(WAF1/CIP1) promoter and coding regions in 10 (34.5%) and 10 (34.5%) of 29 gastric carcinoma specimens, respectively. Hypoacetylation of histone H4 in the p21(WAF1/CIP1) promoter and coding regions was observed in 6 (20.7%) and 16 (55.2%) of 29 gastric carcinoma specimens, respectively. p21(WAF1/CIP1) mRNA levels were associated with histone H3 acetylation status in the p21(WAF1/CIP1) promoter region (p = 0.047) but not p53 mutation status (p = 0.460). In gastric carcinoma cell lines, expression of p21(WAF1/CIP1) protein was induced by trichostatin A, a histone deacetylase inhibitor. This induction was associated with hyperacetylation of histone H3 in the p21(WAF1/CIP1) promoter region. Hyperacetylation of histone H4 in the p21(WAF1/CIP1) promoter region did not appear to be associated with increased expression. Induction of p21(WAF1/CIP1) protein expression was associated with hyperacetylation of histones H3 and H4 in the p21(WAF1/CIP1) coding region. Expression of a dominant-negative mutant of p53 reduced expression of p21(WAF1/CIP1) protein. Histone H4 acetylation in both the promoter and coding regions of the p21(WAF1/CIP1) gene in cells expressing dominant-negative p53 was less than half of that in cells expressing wild-type p53, whereas histone H3 acetylation in both the promoter and coding regions was slightly reduced (by approximately 20%) in cells expressing the dominant-negative p53. These findings provide evidence that alteration of histone acetylation occurs in human cancer tissue specimens such as those from gastric carcinoma.
Acetylation↗
Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma.
Regenerating islet-derived family, member 4 (Reg IV) is a candidate marker for cancer and inflammatory bowel disease. In the present study, immunohistochemical analysis of Reg IV was performed in various human neoplastic (n = 289) and non-neoplastic tissues. In the stomach, foveolar epithelium was negative for Reg IV, whereas goblet cells of intestinal metaplasia and neuroendocrine cells at the base of intestinal metaplasia expressed Reg IV. Neuroendocrine cells of the small intestine and colon showed strong expression of Reg IV, whereas goblet cells of the small intestine and colon showed weak or no expression of Reg IV. Insulin-producing beta cells of the endocrine pancreas were positive for Reg IV. Among 143 gastric adenocarcinomas, Reg IV expression was detected in 42 (29.4%) and was associated with both the intestinal mucin phenotype and neuroendocrine differentiation. No association was found between Reg IV expression and clinical characteristics such as tumour stage and patient prognosis. Of 36 colorectal adenocarcinomas, 13 (36.1%) were positive for Reg IV, which was associated with tumour stage (p = 0.0379, Fisher's exact test). Expression of Reg IV was detected in 14 (93.3%) of 15 colorectal carcinoid tumours. Reg IV expression was also detected in 5 (21.7%) of 23 ductal adenocarcinomas of the pancreas. In contrast, lung cancers (n = 30) and breast cancers (n = 30) did not express Reg IV. This is the first immunohistochemical analysis of the expression and distribution of Reg IV protein in human tumours. These data suggest that Reg IV is expressed by gastrointestinal and pancreatic tumours, including adenocarcinomas and carcinoid tumours, and that Reg IV is associated with intestinal and neuroendocrine differentiation of the stomach and gastric carcinoma.
Adenocarcinoma↗
Molecular-pathological prognostic factors of gastric cancer: a review.
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.
Gene Expression Profiling↗
Cancer and epigenetics--basic research and clinical implications: Joint Meeting of the Fourteenth International Symposium of the Hiroshima Cancer Seminar and the Eighth Meeting of the Tottori Bioscience Promotion Foundation, October 2004.
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Animals↗
DNA methylation profiles of differentiated-type gastric carcinomas with distinct mucin phenotypes.
Gastric carcinomas (GC) are classified into four phenotypes according to mucin expression. Previous studies revealed the association of distinct genetic profiles in GC with mucin phenotypic expression; however, the roles of epigenetic changes, such as DNA methylation, are poorly understood. We examined whether the phenotypic expression of GC was associated with DNA methylation of hMLH1, MGMT, p16(INK4a), RAR-beta or CDH1. Expression of HGM, M-GGMC-1, MUC2, and CD10 was analyzed immunohistochemically in 33 advanced GC with differentiated histology. HGM was expressed in 14 (42.4%) cases, M-GGMC-1 in five (15.2%) cases, MUC2 in 15 (45.5%) cases and CD10 in 18 (54.5%) cases. DNA methylation was detected in five (15.2%) cases for hMLH1, 11 (33.3%) cases for MGMT, 13 (39.4%) cases for p16(INK4a), 17 (51.5%) cases for RAR-beta and 14 (42.4%) cases for CDH1 by bisulfite-polymerase chain reaction and methylation-specific polymerase chain reaction. DNA methylation of hMLH1 occurred more frequently in MUC2-negative GC than in MUC2-positive GC (P = 0.0488, Fisher's exact test). In contrast, MGMT was more frequently methylated in MUC2-positive GC than in MUC2-negative GC (P = 0.0078, Fisher's exact test). There was no correlation between gastric or intestinal-markers and methylation of the p16(INK4a), RAR-beta and CDH1 genes. These results indicate that DNA methylation of specific genes, such as hMLH1 and MGMT, may be involved partly in the distinct phenotypic expression of GC.
Adaptor Proteins, Signal Transducing↗
DNA methylation of genes linked to retinoid signaling in squamous cell carcinoma of the esophagus: DNA methylation of CRBP1 and TIG1 is associated with tumor stage.
Hypermethylation of CpG islands is associated with the silencing of various tumor suppressor genes. Retinoic acid receptor-beta (RAR-beta), cellular retinol-binding protein 1 (CRBP1), and tazarotene-induced gene 1 (TIG1) have been linked to retinoic acid signaling. Little is known about the involvement of these three genes in esophageal squamous cell carcinoma (ESCC). In this study, we investigated the methylation status of these genes and analyzed the role of methylation of their DNA in ESCC. Methylation-specific polymerase chain reaction (PCR) was performed to study the methylation of CpG islands in 28 ESCC (stages I, II, and III) and 10 samples of corresponding non-neoplastic mucosa. The mRNA expression levels of the three genes were measured by quantitative reverse transcription-PCR. DNA hypermethylation of RAR-beta was found in seven (25.0%) of the 28 ESCC, of CRBP1 in five (17.9%), and of TIG1 in five (17.9%). DNA methylation of RAR-beta was identified in one of 10 samples of corresponding non-neoplastic mucosa (10.0%), whereas no DNA methylation of CRBP1 or TIG1 was detected. In total, at least one of the three genes was hypermethylated in 12 (42.9%) ESCC. Reduced expression of RAR-beta, CRBP1, and TIG1 was found in 14 (50.0%), 15 (53.6%), and 13 (46.4%) ESCC, respectively. DNA methylation of each gene was significantly associated with reduced expression of the respective mRNA. No correlation was found between the DNA methylation status of RAR-beta and clinicopathological factors such as depth of invasion, lymph node metastasis, or tumor stage. In contrast, DNA methylation of both CRBP1 and TIG1 was observed only in stage III ESCC. These results show that inactivation of the retinoic acid signaling-associated genes RAR-beta, CRBP1, and TIG1 by DNA methylation occurs frequently in ESCC.
Carcinoma, Squamous Cell↗
Somatic mutations of mitochondrial DNA in digestive tract cancers.
BACKGROUND: Somatic mutations of mitochondrial DNA (mtDNA) have been reported to play an important role in the carcinogenesis of several human cancers. However, there are few reports on mtDNA mutations in digestive tract cancers, including esophageal, gastric and colorectal cancers. The present study examined somatic mtDNA mutations in these cancers. METHODS: Samples of 82 esophageal cancers, 96 gastric cancers and 138 colorectal cancers were collected. Mutations in the D310 mononucleotide repeat of mtDNA were examined by microsatellite assay. RESULTS: Frequencies of mtDNA mutations were similar in each digestive tract cancer: 14% (7/51) in esophageal cancers, 15% (14/94) in gastric cancers and 8% (11/133) in colorectal cancers. There were no significant relationships between mtDNA mutations and clinicopathological features, such as patient age or sex, tumor location, depth of tumor invasion and lymph node metastasis in each digestive tract cancer. CONCLUSIONS: The results suggest that mtDNA mutations play a role in the development but not progression in each digestive tract cancer, and that the role of mtDNA mutations might be similar among the digestive tract cancers.
Aged↗
A single nucleotide polymorphism in the 5' untranslated region of the EGF gene is associated with occurrence and malignant progression of gastric cancer.
OBJECTIVE: Epidermal growth factor (EGF) has many biological functions and plays an important role in the progression of various tumors including gastric cancer. An A-G single nucleotide polymorphism (SNP) at position 61 in the 5'-untranslated region (UTR) of the EGF gene has recently been reported to be associated with different levels of EGF production. We examined whether this polymorphism is correlated with the development and malignant phenotypes of gastric cancer. METHODS: The study population included 200 gastric cancer patients and 230 healthy control subjects. The SNP in the 5'-UTR of the EGF gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The A allele was significantly less frequent in patients than in controls (p = 0.01). Individuals with the A/A or A/G genotype showed a significantly lower risk of gastric cancer than those with the G/G genotype [adjusted odds ratio (OR) = 0.56], whereas the same genotypes were associated with malignant progression of this cancer, e.g. deeper tumor invasion, increased lymph node metastasis and advanced clinical stage, and histological classification in gastric cancer patients (adjusted OR = 1.80, 1.98, 2.26 and 1.89, respectively). CONCLUSIONS: Our findings suggest that the A-G polymorphism of EGF is involved not only in the occurrence but also in the malignant progression of gastric cancer.
5' Flanking Region↗
Genes involved in invasion and metastasis of gastric cancer identified by array-based hybridization and serial analysis of gene expression.
Gastric cancer (GC) is still a serious health problem and remains the second most common type of fatal cancer worldwide. Comprehensive gene expression analyses may be useful to identify genes associated with invasion/metastasis in GC. Among them, array-based hybridization and serial analysis of gene expression (SAGE) are currently the most common approaches. Over the past 3 years, several large-scale gene expression studies with array-based hybridization and SAGE have been performed and several genes have been identified. This review describes genes associated with invasion/metastasis in GC which have been identified by array-based hybridization and SAGE. We compared the expression levels of the genes identified by array-based hybridization with our SAGE data. In addition, expression of the candidate genes obtained by SAGE was further investigated by quantitative RT-PCR of 40 GC samples. MIA and GW112 were overexpressed in 10 (25%) and 22 (55%) of 40 GC samples, and the overexpression of these two genes was associated with tumor stage, respectively. We also discuss the significance of HMGB1/amphoterin in invasion and metastasis of GC.
Blood Proteins↗
[Molecular-pathological diagnosis of gastric cancer].
Gastric cancer is one of the most common human cancers and is the second most frequent cause of cancer-related death in the world. In the course of multistep carcinogenesis of the stomach, various alterations of oncogenes, tumor suppressor genes, DNA repair genes, growth factors/receptors, cell cycle regulators and cell adhesion molecules are accumulated. These can be biological markers of malignancy for molecular-pathological diagnosis. The gene expression profile and scoring system, based on microarray analysis, have great potential for differentiating the character of gene expression in individual cancers and predicting biological behavior and chemosensitivity. Genetic polymorphism is an important determinant of the endogenous cause of cancer and can be used as a marker for gastric cancer risk that will directly connect with personalized cancer prevention. Genetic polymorphisms have been also associated with therapeutic efficacy and toxicity of anti-cancer drugs. Serial analysis of gene expression (SAGE) is a powerful technique to allow genome-wide analysis of gene expression in a quantitative manner. By comparing SAGE libraries of gastric cancer with those of various normal tissues, novel genes specifically expressed in gastric cancer can be selected. If the gene is not expressed in normal crucial organs, the gene can be not only a cancer-biomarker but also a therapeutic target with minimal adverse effects. A custom-made array, based on SAGE libraries, is useful to study the molecular pathogenesis of gastric cancer and obtain information on biological behavior. Combined analyses of gene expression profile and genetic polymorphism will enable the characterization of the individual cancer and person, that is directly connected with personalized medicine and cancer prevention.
Gene Expression Profiling↗
A single nucleotide polymorphism in the extracellular domain of TRAIL receptor DR4 at nucleotide 626 in gastric cancer patients in Japan.
Death receptor 4 (DR4) is a member of the tumor necrosis factor-related apoptosis-inducing ligand receptor genes. A single nucleotide polymorphism (Thr or Arg, C or G) in the extracellular domain was reported to be associated with a risk of lung cancer, head and neck cancer, and bladder cancer. In this study, we examined the association between the DR4 polymorphism and gastric cancer. The Thr/Thr, Thr/Arg and Arg/Arg genotypes were found in 250 (91.2%), 23 (8.4%) and 1 (0.4%) of 274 gastric cancer patients and in 317 (92.2%), 21 (6.1%) and 6 (1.7%) of 344 control subjects, respectively. The OR of Thr/Arg or Arg/Arg genotype did not reveal a significantly enhanced risk of 1.13 (95% CI, 0.63-2.00) compared to Thr/Thr genotype, suggesting that the DR4 polymorphism did not modify the risk of gastric cancer. In patients, no association between the genotype and clinicopathological characteristics (depth of invasion, lymph node metastasis, distant metastasis, stage and grade of differentiation) of gastric carcinoma was found. DR4 was constantly expressed in gastric carcinoma, but not in non-neoplastic gastric epithelium in immunohistochemistry. In conclusion, a Thr to Arg single nucleotide polymorphism in the extracellular domain of DR4 could not be associated with the development and progression of gastric cancer.
Adenocarcinoma↗
No evidence of correlation between the single nucleotide polymorphism of DNMT3B promoter and gastric cancer risk in a Japanese population.
DNA methylation is a major epigenetic modification in humans, and aberrant DNA methylation may play an important role in the development of various cancers through the silencing of some tumor suppressor genes. DNMT3B is required for the establishment and maintenance of genomic methylation patterns. The -149 C/T single nucleotide polymorphism (SNP) in the promoter of DNMT3B has been identified. This SNP influences DNMT3B promoter function, with the T allele having greater activity than the C allele, and is associated with an increased risk of lung cancer. The purpose of our study was to investigate the correlation between the DNMT3B promoter polymorphism and the development and progression of gastric cancer. We analyzed the SNP of the DNMT3B promoter in 152 gastric cancer patients and 247 controls from a Japanese population using PCR-RFLP and sequencing analysis, and also studied the association between the genotypes of DNMT3B and clinicopathological parameters among cases. Allelic difference was not found between gastric cancer patients and control subjects at the target site, -149 bp from the transcriptional start site in the DNMT3B gene promoter. Only the T/T genotype was detected in all gastric cancer patients and control subjects. We concluded that there was no association between SNP of the DNMT3B promoter and gastric cancer risk in a Japanese population.
Case-Control Studies↗
Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma.
Suppressor of cytokine signaling (SOCS)-1 inhibits signaling of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway by several cytokines and has tumor suppressor activity. Methylation of the SOCS-1 CpG island has been shown to inactivate the SOCS-1 gene in certain human cancers. In our study, we investigated methylation status of the SOCS-1 gene by methylation-specific PCR in 75 gastric carcinoma (GC) tissues, 25 corresponding nonneoplastic mucosae and 10 normal gastric mucosae from healthy young individuals. We also performed bisulfite sequencing of DNAs from 2 GC tissues. In addition, SOCS-1 mRNA levels were examined in 50 GCs by quantitative RT-PCR. Hypermethylation of the SOCS-1 gene was detected in 33 (44%) of 75 GC tissues and in 3 (12%) of 25 corresponding nonneoplastic mucosae; the incidence was significantly different (p = 0.004). None of the 10 normal gastric tissues from healthy individuals showed hypermethylation. Methylation of the SOCS-1 gene was associated with lymph node metastasis, advanced tumor stage and reduced expression of SOCS-1 in GC tissues (p = 0.009, 0.034 and 0.002, respectively). Reduced expression of SOCS-1 in GC tissues was associated with lymph node metastasis and advanced tumor stage (p = 0.013 and 0.002, respectively). Our results suggest that transcriptional inactivation of the SOCS-1 gene by hypermethylation may be involved in development, progression and metastasis of GC.
Carcinoma↗
ADAM8 as a novel serological and histochemical marker for lung cancer.
PURPOSE AND EXPERIMENTAL DESIGN: We have been investigating genes involved in pulmonary carcinogenesis by examining gene expression profiles of non-small-cell lung cancers to identify molecules that might serve as diagnostic markers or targets for development of new molecular therapies. A gene encoding ADAM8, a disintegrin and metalloproteinase domain-8, was selected as a candidate for such molecule. Tumor tissue microarray was applied to examine expression of ADAM8 protein in archival lung cancer samples from 363 patients. Serum ADAM8 levels of 105 lung cancer patients and 72 controls were also measured by ELISA. A role of ADAM8 in cellular motility was examined by Matrigel assays. RESULTS: ADAM8 was abundantly expressed in the great majority of lung cancers examined. A high level of ADAM8 expression was significantly more common in advanced-stage IIIB/IV adenocarcinomas than in adenocarcinomas at stages I-IIIA. Serum levels of ADAM8 were significantly higher in lung cancer patients than in healthy controls. The proportion of the serum ADAM8-positive cases defined by our criteria was 63% and that for carcinoembryonic antigen was 57%, indicating equivalent diagnostic power of these two markers. A combined assay using both ADAM8 and carcinoembryonic antigen increased sensitivity because 80% of the lung cancer patients were then diagnosed as positive, whereas only 11% of 72 healthy volunteers were falsely diagnosed as positive. In addition, exogenous expression of ADAM8 increased the migratory activity of mammalian cells, an indication that ADAM8 may play a significant role in progression of lung cancer. CONCLUSIONS: Our data suggest that ADAM8 should be useful as a diagnostic marker and probably as a therapeutic target.
ADAM Proteins↗
Characterization of vitamin D-mediated induction of the CYP 24 transcription.
Transcription of the CYP24 (25-hydroxyvitamin D(3)-24-hydroxylase) gene is known to be induced by 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). We studied the induction kinetics in detail in human skin-derived fibroblasts. While the basal transcription of this gene was very low, addition of 1,25(OH)2D3 increased the mRNA level by 50-fold within 1h. The induction reached as high as 20000-fold after 12h. DNA microarray analysis also indicated that the induction ratio of the CYP24 gene is exceptionally high among 3800 human genes examined. The increase of mRNA was caused by stimulation of the transcription, but not by stabilization of mRNA. 24(R),25-dihydroxyvitamin D3 (24,25(OH)2D3), a compound metabolically related to 1,25(OH)2D3, also stimulated the CYP24 gene transcription, though at much higher concentrations. However, this stimulation was significantly augmented by synergistic actions of 24,25(OH)2D3 and 1,25(OH)2D3, suggesting that 24,25(OH)2D3 or its metabolites might be playing some roles in the regulation of CYP24 gene transcription.
24,25-Dihydroxyvitamin D 3↗
A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer.
PURPOSE: Matrix metalloproteinase-9 (MMP-9, gelatinase B) plays a key role in cancer invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane barriers. A cytosine (C)-thymidine (T) single nucleotide polymorphism (SNP) at position -1562 in the MMP-9 promoter is reported to affect expression of this gene. The purpose of this study was to investigate the relation between the -1562 C/T polymorphism and the development and progression of gastric cancer. METHODS: The study population included 177 gastric cancer patients and 224 healthy control subjects. The SNP in the MMP-9 promoter was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological features was studied. RESULTS: Genotype frequencies in gastric cancer patients were similar to those in control subjects (P = 0.223). However, significant association was found between degree of tumor invasion, clinical stage, and lymphatic invasion and the MMP-9 polymorphism in gastric cancer patients (P<0.05, for each). CONCLUSIONS: Our results indicate that the T allele in the MMP-9 promoter is associated with the invasive phenotype of gastric cancer.
Aged↗