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W Yasui

Publications and source records attributed to W Yasui.

At least 19 recordsLinked to original sources
PubMed2006

Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer.

Gastric cancer (GC) is one of the most common malignancies worldwide. Genes expressed only in cancer tissue will be useful molecular markers for diagnosis and may also be good therapeutic targets. However, little is known about cancer-specific genes, at least in GC. In this study, we searched for GC-specific genes by serial analysis of gene expression (SAGE) data analysis and quantitative reverse transcription (RT)-PCR. Comparing GC SAGE libraries with those of various normal tissues in the SAGEmap database, we identified 54 candidate GC-specific genes. Quantitative RT-PCR analysis of these candidates revealed that APin protein (APIN), taxol resistance-associated gene 3 (TRAG3), cytochrome P450, family 2, subfamily W, polypeptide 1 (CYP2W1), melanoma inhibitory activity (MIA), matrix metalloproteinase-10 (MMP-10), dickkopf homolog 4 (DKK4), GW112, regenerating islet-derived family, member 4 (REGIV), and HORMA domain-containing 1 (HORMAD1) were expressed much more highly in GC than in 14 kinds of normal tissues. Immunohistochemical staining for MIA, MMP-10, and DKK4 was found in 47 (31.1%), 68 (45.0%), and two (1.3%) of 151 GCs, respectively, and staining for both MIA and MMP-10 was correlated with poor prognosis in advanced GC (P=0.0001 and 0.0141, respectively). Moreover, enzyme-linked immunosorbent assay showed high levels of MMP-10 (65/69, 94.2%) in serum samples from patients with GC. Levels of MIA were raised in a small proportion of serum samples from patients with GC (4/69, 5.8%). In Boyden chamber invasion assays, MIA-transfected GC cells were up to three times more invasive than cells transfected with empty vector. Taken together, these results suggest that MMP-10 is a good marker for the detection of GC and that MIA and MMP-10 are prognostic factors for GC. As expression of MIA and MMP-10 is narrowly restricted in cancer, these two molecules may be good therapeutic targets for GC.

Adult↗
PubMed2006

Down-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype.

Gastric cancer (GC) is one of the most common malignancies worldwide. Genes whose expression is down-regulated in GC may be tumour suppressor genes. In the present study, genes with decreased expression in GC were screened for by serial analysis of gene expression (SAGE) data analysis and reverse transcription (RT)-polymerase chain reaction (PCR), and CLDN18 (encoding claudin-18) was identified. Quantitative RT-PCR revealed that expression of CLDN18 was down-regulated in 13 (56.5%) of 23 GCs. Immunostaining showed that normal gastric mucosa and Paneth cells of the duodenum expressed claudin-18 on cell membranes. Expression of claudin-18 was reduced in several intestinal metaplasias of the stomach. Of 20 samples of gastric adenoma, 18 (90.0%) showed decreased claudin-18 expression. Down-regulation of claudin-18 was observed in 84 of 146 GCs (57.5%) and correlated with poor survival in 65 advanced GCs (p = 0.0346). In addition, expression of the gastric and intestinal phenotypes of GC was examined by immunostaining for MUC5AC, MUC6, MUC2, and CD10. Of 38 GCs showing only the intestinal phenotype, down-regulation of claudin-18 was observed in 28 (73.7%), whereas in the remaining 108 GC cases, down-regulation of claudin-18 was observed in 56 (51.9%) (p = 0.0224). These results indicate that claudin-18 is a good marker of poor survival in GC. Down-regulation of claudin-18 may be involved in GCs with an intestinal phenotype, and may be an early event in gastric carcinogenesis.

Adenocarcinoma↗
PubMed2006

Nuclear and mitochondrial DNA microsatellite instability in gastrointestinal stromal tumors.

OBJECTIVE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Nuclear (nMSI) and mitochondrial microsatellite instability (mtMSI) play important roles in tumorigenesis in various organs. The aim of this study was to evaluate the role of nMSI and mtMSI in GISTs. METHODS: Samples from 74 mesenchymal tumors were collected. nMSI and mtMSI were examined by microsatellite assay at BAT26 and D310 mononucleotide repeats in mtDNA, respectively. We compared nMSI, mtMSI and clinicopathologic features, including patient age and sex, tumor location, tumor size, presence of tumor ulceration and presence of distant metastasis, for 51 GISTs for which these data were available. RESULTS: nMSI and mtMSI were detected in 3 (5%) and 10 (16%) of the 62 GISTs, respectively. There was no significant relationship between nMSI, mtMSI and clinicopathologic features. CONCLUSION: These results suggest that mtMSI may play a role, but that nMSI may play little role in the development of GISTs.

Adult↗
PubMed2005

Morphological changes in human gastric tumours after eradication therapy of Helicobacter pylori in a short-term follow-up.

BACKGROUND: It is controversial as to whether the development of gastric cancer is influenced by Helicobacter pylori eradication. If eradication itself influences the tumour morphology, this may affect the tumour discovery rate. AIM: To investigate the morphological changes in the gastric neoplasm after H. pylori eradication. METHODS: We studied 37 patients with eradication therapy. After a 1-month follow-up, endoscopic re-evaluation was performed and the appearance was compared with first image. All lesions were resected endoscopically, and were subjected to histological assessment and to immunohistochemistry. Serum gastrin levels were determined before and after eradication. RESULTS: Twenty-nine of 37 patients underwent successful eradication. The appearance of 11 lesions (33% of 33 lesions) became indistinct after successful eradication. All lesions were of the superficial-elevated type and the height of the lesions decreased. We detected normal columnar epithelium over the neoplasm in eight of the lesions. Higher expression of single-stranded deoxyribonucleic acid in the deep area was characteristic in tumours with an indistinct appearance. These changes did not correlate with the serum gastrin levels. CONCLUSIONS: The morphology of the gastric neoplasm change after eradication in the short-term. This may contribute to the decreased tumour discovery rate.

Adenocarcinoma↗
PubMed2004

Lack of vascular adventitial fibroblastic cells in tumour stroma of intestinal-type and solid-type gastric carcinomas.

AIMS: To investigate the roles of vascular adventitial fibroblastic cells in tumour stroma, the distribution of vascular adventitial fibroblastic cells was studied in gastric carcinomas. METHODS: In total, 50 surgically resected gastric carcinomas (43 intestinal type, and seven solid type) and their normal tissues were examined. Vascular adventitial fibroblastic cells are positive for CD34 but negative for CD31. To differentiate vascular adventitial fibroblastic cells from vascular endothelial cells, immunostaining for CD34 and CD31 was performed. Immunostaining for high molecular weight caldesmon was also performed to recognise vascular media. RESULTS: In normal gastric tissues, CD34 positive fibroblastic cells were found just outside the vascular media, namely vascular adventitial fibroblastic cells. In contrast, all of the 43 intestinal-type and seven solid-type gastric carcinomas had no vascular adventitial fibroblastic cells in the tumour stroma. CONCLUSIONS: These results suggest that a lack of vascular adventitial fibroblastic cells is associated with tumour stroma formation in intestinal-type and solid-type gastric carcinomas.

Antigens, CD34↗
PubMed2004

Adenocarcinoma arising from a gastric duplication cyst with invasion to the stomach: a case report with literature review.

This report describes a rare case of adenocarcinoma arising from a gastric duplication cyst, with invasion to the stomach wall, in a 40 year old Japanese man. A cystic lesion was found between the stomach and the spleen. The cyst had a well circumscribed smooth muscle layer, corresponding to the muscularis propria of the stomach and the mucosa of the alimentary tract. A well differentiated adenocarcinoma was found within the duplication cyst, invading its serosa. Well differentiated adenocarcinoma was independently found in the fundus of the stomach; the tumour of the cyst was connected by fibrous tissue. Microscopically, there was neither adenocarcinoma in situ nor precancerous lesions, such as epithelial dysplasia, suggesting that the carcinoma derived from a gastric duplication cyst that invaded the stomach. Duplication cysts should be included in the differential diagnosis of cystic masses of the gastrointestinal tract, and the possibility of malignancy within these cysts should be considered.

Adenocarcinoma↗
PubMed2004

High molecular weight caldesmon positive stromal cells in the capsule of hepatocellular carcinomas.

AIMS: To investigate the smooth muscle nature of the stromal cells in the capsule of hepatocellular carcinomas. METHODS: Immunohistochemical analysis using monoclonal antibody to high molecular weight caldesmon (HCD), a highly specific marker for smooth muscle cells, was performed in 33 encapsulated hepatocellular carcinomas and adjacent hepatic tissues. RESULTS: HCD positive stromal cells were detected in the capsule of 21 of the 33 hepatocellular carcinomas examined. CONCLUSIONS: The capsule of hepatocellular carcinomas contains smooth muscle cells.

Antibodies, Monoclonal↗
PubMed2004

Presence of vascular adventitial fibroblastic cells in diffuse-type gastric carcinomas.

AIM: To investigate morphological changes in the tumour vessel adventitia, particularly the distribution of vascular adventitial fibroblastic cells (VAFCs)--namely, CD34 positive fibroblastic cells just outside the vascular media--in diffuse-type gastric carcinomas. METHOD: In total, 18 surgically resected advanced typical diffuse-type gastric carcinomas and their normal tissues were examined. Immunostaining for CD34, CD31, high molecular weight caldesmon (HCD), and cytokeratin 8 (CAM5.2) was performed to detect VAFCs. VAFCs are positive for CD34 but negative for CD31, and are located just outside the vascular media (HCD positive vascular smooth muscle bundle). The areas just outside the vascular media in the whole maximum tumour cut surface were assessed, except the tumour growing edge, which was confirmed by immunostaining with CAM5.2. CD34 positive and CD31 negative cells just outside the vascular media were defined as VAFCs. RESULTS: VAFC containing vessels were seen in 17 of the 18 diffuse carcinoma tissues. Vessels lacking VAFCs were also detected in these 17 tumours. In contrast, all of the vessels lacked VAFCs in the remaining tumour. In the 18 samples of normal tissue, all of the vessels contained VAFCs. CONCLUSIONS: These results suggest that the presence of VAFCs is associated with the infiltration of diffuse scattered gastric carcinoma cells.

Adenocarcinoma↗
PubMed2002

Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa.

We examined the relationship between vascular endothelial growth factor (VEGF)-C expression and lymph node metastases in gastric carcinomas invading the submucosa. Of the six human gastric carcinoma cell lines, two constitutively expressed VEGF-C mRNA. In three of 12 gastric biopsy specimens (25%), VEGF-C mRNA was detected in tumour tissues, but not in corresponding normal mucosa by reverse transcriptase-polymerase chain reaction (RT-PCR). Of the 139 resected gastric carcinomas, 44 (32%) showed intense cytoplasmic VEGF-C immunoreactivity in many cancer cells at the invading edge. VEGF-C immunoreactivity was associated with greater depth of tumour invasion, lymphatic invasion and lymph node metastases. In addition, vessel count was also significantly higher in the VEGF-C immunoreactive tumours than in other tumours. These results suggest that VEGF-C may be involved in the progression of human gastric carcinoma, particularly via lymphangiogenesis. VEGF-C expression at the invading edge of a gastric carcinoma may be a sensitive marker for metastasis to the lymph nodes.

Blotting, Northern↗
PubMed2002

Acetylated histone H4 is reduced in human gastric adenomas and carcinomas.

Acetylation of core histones is closely linked to transcriptional activation of various genes. The acetylation levels of nucleosomal histones can be modified through a balance of histone acetyltransferases and deacetylases. To elucidate the role of histone acetylation in human gastric carcinogenesis, we studied the status of histone H4 acetylation in gastric carcinoma tissues and corresponding non-neoplastic mucosa. The status of histone acetylation was assessed by examining the expression of acetylated histone H4 through Western blotting and immunohistochemistry using an anti-acetylated histone H4 antibody. The levels of acetylated histone H4 expression were obviously reduced in 72% (13/18) of gastric carcinomas in comparison with non-neoplastic mucosa by Western blotting. In immunohistochemistry, acetylated histone H4 was clearly detected in the nuclei of both non-neoplastic epithelial and stromal cells, whereas the levels of acetylated histone H4 were heterogeneous or reduced in 66% (38/57) of gastric carcinomas and 46% (6/13) of gastric adenomas. Reduced expression of acetylated histone H4 was also observed in some areas of intestinal metaplasia adjacent to carcinomas. Reduction in the expression of acetylated histone H4 was significantly correlated with advanced stage, depth of tumor invasion and lymph node metastasis. These results suggest that low levels of histone acetylation may be closely associated with the development and progression of gastric carcinomas, possibly through alteration of gene expression.

Acetylation↗
PubMed2001

Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus.

Neoplastic progression in Barrett's esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barrett's esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27(kip1) protein, but did not display appreciable nuclear staining for p16(kip4), p21(cip1) or cyclins D1 and E. Barrett's metaplastic specimens displayed increased expression levels of p16(kip4) (74%), p21(cip1) (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16(kip4) and cyclin E, and p21(cip1) and p27(kip4) with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barrett's esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.

Adult↗
PubMed2001

Interferon-alpha prevents selection of doxorubicin-resistant undifferentiated-androgen-insensitive metastatic human prostate cancer cells.

BACKGROUND: We determined whether treatment of metastatic prostate cancer cells with doxorubicin (DOX) and interferon-alpha (IFN-alpha) prevented the emergence of highly undifferentiated tumor cells. METHODS: The state of cell differentiation was determined by analysis of prostate-specific antigen (PSA), E-cadherin, keratin, and vimentin. RESULTS: Human prostate cancer LNCaP-LN3 cells growing in culture as multicell spheroids expressed higher levels of E-cadherin and E-cadherin-associated beta-catenin than LNCaP-LN3 cells growing as monolayers. Treatment of cells with DOX downregulated PSA, E-cadherin, and keratin, and upregulated expression of vimentin and vascular endothelial growth factor (VEGF) mRNA. While treatment of cells with IFN-alpha did not alter gene expression, the addition of IFN-alpha to cultures treated with DOX produced synergistic toxicity and abrogated the changes in gene expression observed in cells treated with DOX alone. CONCLUSIONS: Treatment with IFN-alpha and DOX should be further explored as a therapeutic strategy for androgen-insensitive prostate cancer.

Androgens↗
PubMed2001

Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas.

The purpose of this study was to investigate the expression of vascular endothelial growth factor (VEGF) -C in human esophageal squamous cell carcinomas to elucidate its role in lymph node metastasis and tumor progression. The expression of VEGF-C and flt-4 genes was examined in 5 esophageal carcinoma cell lines, 12 fresh biopsy specimens and 48 archival surgical specimens of human esophageal carcinoma tissues by RT-PCR and immunohistochemistry. Immunohistochemistry using antibodies against CD34 (endothelial cell specific) was also carried out and microvessels were quantified by counting vessels in a 200x field in the most vascular area of the tumor. Of the 5 human esophageal carcinoma cell lines, 4 constitutively expressed VEGF-C mRNA. In 8 (66.7%) of 12 cases, VEGF-C mRNA was detected in only tumor tissues but not in normal mucosa by RT-PCR. There was a significant relationship between VEGF-C and flt-4 mRNA expression. Out of the 48 surgical specimens of esophageal carcinomas, 19 (39.6%) and 10 (20.8%) exhibited intense VEGF-C immunoreactivity in the cytoplasm of many cancer cells and the stromal cells, respectively. In contrast, Flt-4 was mainly expressed on the lymphatic endothelial cells. Normal and dysplastic esophageal squamous epithelium exhibited no or faint cytoplasmic staining of VEGF-C. VEGF-C expression correlated with depth of tumor invasion, tumor stage, venous invasion, lymphatic invasion and lymph node metastasis. Vessel count was significantly higher in the VEGF-C positive tumors than in the negative tumors. These results overall suggest that VEGF-C may play a role in tumor progression via lymphangiogenesis and angiogenesis in human esophageal carcinoma.

Carcinoma, Squamous Cell↗
PubMed2001

Promoter hypermethylation of MGMT is associated with protein loss in gastric carcinoma.

Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumor suppressor genes in neoplasms. Recently, O(6)-methylguanine-DNA methyltransferase, MGMT, was shown to be hypermethylated in certain carcinomas, resulting in loss of MGMT protein. We studied DNA methylation of CpG islands of the MGMT gene by methylation specific PCR in 26 gastric carcinoma tissues and 8 gastric carcinoma cell lines for comparison with levels of MGMT protein expression. In addition, we examined p53 mutation status in the same tissues by PCR-SSCP analysis for comparison with MGMT protein expression levels. In total, promoter hypermethylation of the MGMT gene was found in 8 (31%) of the 26 gastric carcinomas with reduced expression of MGMT protein, whereas the hypermethylation was not detected in the 18 carcinomas with non-reduced MGMT expression. MGMT protein expression levels were associated with promoter hypermethylation of MGMT (p = 0.0001; Mann-Whitney test); however, MGMT expression was not associated with p53 mutation status (p = 0.461; Mann-Whitney test). Among in gastric carcinoma cell lines, the TMK-1 cell line showed loss of the MGMT protein association with promoter hypermethylation and this loss was rectified by treatment with a demethylating agent, 5-Aza-2'-deoxycytidine. Our results suggest that transcriptional inactivation of MGMT by aberrant methylation of the promoter region may participate in carcinogenesis in the stomach.

Alleles↗
PubMed2001

Molecular diagnosis of gastric cancer: present and future.

Although histopathological diagnosis is extremely useful for the definitive as well as the supportive diagnosis of gastric cancer in clinical practice, it is limited in certain respects. Over the past 15 years, integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of the development and progression of gastric cancer. These abnormalities, which include telomerase activation, genetic instability, and abnormalities in oncogenes, tumor suppressor genes, cell-cycle regulators, cell adhesion molecules, and DNA repair genes, could be effective markers in the molecular diagnosis of gastric cancer. It is possible that the molecular analysis of these alterations in histopathology specimens may overcome deficiencies in diagnoses that depend only on histomorphology, and, consequently, we may be able to improve the differential diagnosis of cancer, obtain information on the grade of malignancy, and identify patients at high risk of developing multiple primary cancers. In Hiroshima, we have established a system of molecular-pathological diagnosis as a routine service; about 5,000 lesions of the stomach have been subjected to this diagnosis, and much useful information has been obtained. In the near future, genetic analysis by means of DNA microarray may become routine in the diagnosis of gastric cancer. Genetic analysis of histopathology specimens may make clear the characteristics of individual cancers; indicating the common and specific features of molecular pathogenesis that may be directly connected with gene therapy or molecular-targeted therapy. By analyzing the relationship between single-nucleotide polymorphisms and cancer susceptibility, we will be able to obtain information on cancer prevention from histopathology samples.

Adenocarcinoma↗
PubMed2001

Genetic and epigenetic changes in stomach cancer.

Genetic and epigenetic alterations of multiple cancer-related genes and molecules are implicated in the development and progression of human gastric carcinomas. Reactivation of telomerase, inactivation of p53 tumor suppressor gene, overexpression of cyclin E, and reduced expression of p27 KIP1 by disorganized degradation in proteasome are common events of both well-differentiated and poorly differentiated gastric adenocarcinomas. Inactivation of hMLH1 mismatch repair gene by CpG hypermethylation resulting in microsatellite instability, amplification of c-erbB2 oncogene, inactivation of APC tumor suppressor gene, and K-ras mutations are preferentially associated with well-differentiated gastric cancer. Conversely, reduction or loss of E-cadherin and catenins by both mutation and CpG hypermethylation and K-sam and c-met oncogene amplification are necessary for the development and progression of poorly differentiated or scirrhous gastric carcinomas. Interaction between cancer cells expressing c-met and hepatocyte growth factor from stromal cells is implicated in morphogenesis of gastric cancer.

Animals↗
PubMed2001

Inactivation of retinoic acid receptor beta by promoter CpG hypermethylation in gastric cancer.

Inactivation of nuclear retinoic acid receptor beta (RARbeta) expression is implicated in tumorigenesis. We hypothesized that loss of RARbeta in gastric cancer cells may occur as a result of multiple factors, including epigenetic modifications which alter RARbeta promoter chromatin structure. We examined hypermethylation of CpG islands present in the RARbeta promoter by methylation-specific PCR and the expression of RARbeta in gastric cancer cell lines and tissues. Three (MKN-28, -45 and -74) out of eight gastric cancer cell lines had a loss of RAR expression associated with promoter methylation. RARbeta expression was retrieved in these cell lines by treatment with 5-azacytidine or by the histone deacetylase inhibitor trichostatin A. Promoter hypermethylation was detected in 64% (7/11) of gastric carcinoma tissues with reduced expression of RARbeta, whereas it was detected in 22% (2/9) of tumors with retained RARbeta expression. To investigate the functions of exogenous RARbeta in gastric cancer cells, we transfected a retroviral RARbeta expression vector (LNSbeta) into MKN-28 cells that have hypermethylation of the RARbeta promoter. Overexpression of RAR in MKN-28 cells appeared to regulate the expression of DNA methyltransferase and DNA demethylase and the acetylation of hitone H4. These results suggest that the transcriptional inactivation of the RARbeta by promoter CpG hypermethylation is frequently associated with gastric carcinoma. Our data also suggests that DNA methylation plays a pivotal role in establishing and maintaining an inactive state of RARbeta by rendering the chromatin structure inaccessible to the transcription machinery.

Aged↗