Biomedical subjects

Teiichi Motoyama

Publications and source records attributed to Teiichi Motoyama.

At least 19 recordsLinked to original sources

PubMed2004

Demethylation of the synuclein gamma gene CpG island in primary gastric cancers and gastric cancer cell lines.

PURPOSE: Whereas synuclein gamma (SNCG) gene expression is usually highly tissue-specific and restricted to the nervous system, SNCG is expressed in advanced-stage breast and ovarian cancers. When overexpressed, SNCG stimulates cancer cell proliferation and metastasis. It is thought that the molecular mechanism of CpG island demethylation may underlie aberrant SNCG expression. To determine whether aberrant SNCG expression and demethylation play a role in gastric carcinogenesis, we examined the expression and methylation status of SNCG in primary gastric cancers, gastric cancer cell lines, and non-neoplastic gastric mucosal tissues. EXPERIMENTAL DESIGN: Ten gastric cancer cell lines, 105 primary gastric cancers, and 10 non-neoplastic gastric mucosal tissues were examined. SNCG expression and methylation status were examined by reverse transcription-PCR and bisulfite-single-strand conformational polymorphism followed by direct sequencing, respectively. The relationship between SNCG methylation status and various clinicopathological factors of the primary gastric cancers was then analyzed. RESULTS: SNCG mRNA expression was observed in 5 of 10 cell lines. Analysis of cell lines positive for SNCG expression revealed that most of the SNCG CpGs were demethylated. SNCG mRNA was not expressed in the 10 non-neoplastic gastric mucosal tissues, although several CpGs were demethylated. Of the 105 primary gastric cancers, 40 (38.1%) showed apparent SNCG demethylation, similar to the result obtained using cell lines. SNCG demethylation was more frequent in primary gastric cancers positive for lymph node metastasis (51%; 26 of 51) than in cancers without lymph node involvement (26%; 14 of 54; P < 0.05), and also more common in stage II-IV (48%; 27 of 56) than in stage I (27%; 13 of 49) cancers (P < 0.05). CONCLUSIONS: Aberrant SNCG gene expression can occur via CpG island demethylation, and tends to occur during the more progressive stages of gastric carcinogenesis.

Adult↗

PubMed2004

Inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models.

Whether or not inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models was investigated. We compared the basal levels of phosphorylation of IkappaBalpha and activity of NFkappaB between cisplatin-sensitive A2780 cells and cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation of IkappaBalpha and activity of NFkappaB in Caov-3 cells were significantly higher than those in A2780 cells. Cisplatin caused a more marked decrease in the phosphorylation of IkappaBalpha and activity of NFkappaB in A2780 cells than in Caov-3 cells. Thus, high basal levels of phosphorylation of IkappaBalpha and activation of NFkappaB and less marked inhibition of the phosphorylation of IkappaBalpha and activation of NFkappaB by cisplatin seem to reduce the sensitivity of cells to cisplatin. Inhibition of NFkappaB activity either by treatment with the IkappaBalpha phosphorylation inhibitor (BAY 11-7085) or a specific NFkappaB nuclear translocation inhibitor (SN-50) or by transfection of p50DeltaNLS (which lacks the nuclear localization signal domain) increased the efficacy of both the cisplatin-induced attenuation of IkappaBalpha phosphorylation and NFkappaB activity and the cisplatin-induced apoptosis. In addition, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced attenuation of both the expression of X-linked inhibitor of apoptosis protein (XIAP) and cell invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced inhibition of the intra-abdominal dissemination and production of ascites using athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that combination therapy of cisplatin with the NFkappaB inhibitor should increase the therapeutic efficacy of cisplatin.

Animals↗

PubMed2004

Expression of a transcription factor, SOX9, in Sertoli-stromal cell tumors of the ovary.

Two cases of ovarian Sertoli-stromal cell tumor were examined for expression of a transcription factor, SOX9, which plays an essential role in Sertoli cell differentiation, downstream of Sry, as in the testis. By reverse transcriptase polymerase chain reaction, SOX9 mRNA was expressed in both tumors, despite the absence of Sry. These findings suggest that SOX9 expression probably plays some role in Sry-independent testicular differentiation in ovarian Sertoli-stromal cell tumors.

Adolescent↗

PubMed2003

Histogenesis of hepatoid adenocarcinoma of the stomach: molecular evidence of identical origin with coexistent tubular adenocarcinoma.

Hepatoid adenocarcinoma of the stomach is a highly malignant neoplasm. Most gastric hepatoid adenocarcinomas coexist with tubular adenocarcinoma. However, the relationship between hepatoid adenocarcinoma and tubular adenocarcinoma is still unclear. In the present study, the characteristics of the coexistent tubular adenocarcinomas were determined by examining their profiles of mucin production. Subsequently, molecular pathological techniques were applied to determine the clonality of 15 mixed hepatoid and tubular adenocarcinomas of the stomach. Mucin analysis suggested that the coexistent tubular adenocarcinomas with hepatoid adenocarcinoma were of the intestinal type. The patterns of chromosome X inactivation were identical between the hepatoid adenocarcinoma component and tubular adenocarcinoma component in all of 3 informative female cases. Mutations in the p53 gene were found in 5 cases. The sequences were identical within both tumor components in all 5 cases. Microsatellite analysis indicated more than 3 common patterns of loss of heterozygosity in 8 cases. These observations strongly suggested that hepatoid adenocarcinomas were of identical origin to coexistent tubular adenocarcinomas.

Adenocarcinoma↗

PubMed2003

Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples.

Age-related methylation may have the potential to behave as a mutator process. To clarify the physiological consequence of age-related methylation of tumor suppressor and tumor-related genes, we studied promoter methylation status in non-neoplastic cells of various organs obtained at autopsy by methylation-specific PCR. Promoter methylation status of APC, DAP-kinase, E-cadherin, GSTP1, hMLH1, p16, RASSF1A and RUNX3 genes, which are frequently silenced in certain human malignancies, was studied in non-neoplastic cells of the esophagus, stomach, small and large intestines, liver, pancreas, kidney and lung obtained from 38 Japanese autopsies. The tumor suppressor and tumor-related genes, except APC and RASSF1A, were generally unmethylated in samples obtained from people who were less than 32 years old (n=11). Methylated promoters were present at variable frequencies in a tissue-specific manner in samples obtained from people who were greater than 42 years old (n=27), although GSTP1 and hMLH1 methylation was absent or infrequent and lacked tissue specificity. In the majority of organs, the incidence of age-related methylation paralleled the reported methylation incidence in malignant counterparts. Thus, age-related methylation of a different set of genes is thought to constitute a field defect in different organs.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Hypermethylation of the RUNX3 gene promoter in testicular yolk sac tumor of infants.

Testicular yolk sac tumor (YST) of infants is biologically distinct from its adult counterpart. Cytogenetically, YSTs in infants generally lack i(12p), which is highly characteristic of adult germ cell tumors (GCTs), whereas they frequently show a deletion of 1p36, indicating that the loss of a certain gene(s) in this region is an important event in the pathogenesis of infantile YSTs. In the present study, we examined 10 testicular YSTs from infants for promoter methylation status of the RUNX3 gene, localizing in 1p36.1, and loss of heterozygosity (LOH) in this region, on the presumption that RUNX3 acts as a tumor suppressor. Methylation of RUNX3 and LOH at 1p36.1 were detected in 8 of 10 (80%) and 6 of 8 (75%) infantile YSTs examined, respectively. All six cases harboring LOH showed RUNX3 methylation. In contrast, 0 of 12 adult GCTs showed RUNX3 methylation, and LOH at 1p36.1 was less frequent (1 of 6 cases: 16%) in adult GCTs. There is a significant difference in RUNX3 methylation between these 2 groups (P < 0.001). In normal testes of the young group, RUNX3 methylation was not detected. These results strongly suggest that RUNX3 is one of the tumor suppressors involved in the pathogenesis of testicular YSTs in infants.

Adult↗

PubMed2003

Ovarian carcinoid exhibiting double function.

A case of a 58-year-old woman with ovarian carcinoid exhibiting double function is reported. She had suffered from constipation and hirsutism before surgery. Pathological examination revealed that many carcinoid tumor cells were immunohistochemically positive for peptide YY, which inhibits intestinal motility and many peripheral steroid cells. After surgery the patient recovered from constipation immediately. Although the serum level of testosterone also immediately decreased, hirsutism remained for about 2 years. These clinical manifestations are considered to be due to peptide hormone-producing tumor parenchymal cells and testosterone-producing functioning stromal cells. This is the first report of clinically manifested double-functioning ovarian carcinoid; one function is due to tumor cells themselves and another function is due to stromal cells.

Biomarkers, Tumor↗

PubMed2003

Microsatellite instability in esophageal squamous cell carcinoma is not associated with hMLH1 promoter hypermethylation.

To test whether a subset of esophageal squamous cell carcinomas (SCC) develop through a deficiency in DNA mismatch repair, we examined microsatellite instability (MSI) using 11 microsatellite markers including BAT-26, hMLH1 protein expression by immunohistochemistry, and methylation status of the hMLH1 promoter by methylation-specific polymerase chain reaction (MSP). p53 mutations were also investigated. Microsatellite instability at one or more loci was observed in 40% (12/30) of esophageal SCC tumor samples, although only one of these tumors was categorized as high-frequency MSI (MSI-H) and none showed BAT-26 instability. While immunohistochemistry revealed decreased hMLH1 protein expression in 27% (8/30) of the tumors, hMLH1 promoter hypermethylation was not observed. Absence of hMLH1 protein expression was relatively common in well-differentiated (keratinizing-type) esophageal SCC, but was not associated with hMLH1 promoter hypermethylation. p53 mutation was detected in 37% (11/30) and loss of heterozygosity (LOH) in 90% (27/30) of esophageal SCC samples. Our results suggested that most esophageal SCC develop through defects in tumor suppressor genes (i.e. the suppressor pathway), and that MSI in esophageal SCC probably represent random replication errors rather than being associated with DNA mismatch repair deficiency.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Genetic analysis of cutaneous squamous cell carcinomas arising from different areas.

Although cutaneous squamous cell carcinomas (SCC) occur most frequently in sun-exposed areas of the skin, they can also arise in non-sun-exposed areas. Some risk factors for cutaneous SCC, such as ultraviolet (UV) light, are well known. However, the major factor for carcinogenesis may depend on the site of the tumor as well as the ethnicity of the patient. In this study we examined 41 Japanese cutaneous SCC cases, focusing on the area of appearance and the presence of genetic alteration, with 27 cases from sun-exposed areas, 10 from non-sun-exposed areas (excluding genital areas), and four from burn scars from sun-exposed areas. Squamous cell carcinomas arising in sun-exposed areas showed less frequent p53 gene mutations compared to SCC arising in non-sun-exposed areas. Ultraviolet light-specific mutations were found in only two cases of SCC from sun-exposed areas. Human papilloma virus (HPV) DNA was detected in two cases (7.4%) of the sun-exposed areas and none of the non-sun-exposed or scar areas. The frequency of loss of heterozygosity on D5S178 in non-sun-exposed SCC was significantly higher than in sun-exposed SCC. Furthermore, the incidence of fractional allelic loss (FAL) was significantly higher in non-sun-exposed SCC than in sun-exposed SCC. Our findings suggest that sun-exposed SCC in Japan may be relatively less involved with p53 mutation, and that non-sun-exposed SCC acquire more genetic alterations than sun-exposed SCC.

Adult↗

PubMed2003

Primary carcinoid tumor of the testis: Immunohistochemical, ultrastructural and FISH analysis with review of the literature.

Primary carcinoid tumor of the testis only accounts for 0.2% of all carcinoid tumors in Japan. The clinicopathological features, including differences between Japanese and Europe/United States (Eur/US) series', which are known in ovarian carcinoids, have not yet been sufficiently recognized. In the present study, five testicular carcinoids from various clinicopathological viewpoints were analyzed, with a review of the literature. All 15 cases in Japan, including 10 previously reported, were insular carcinoids. Three of the 15 cases (20%) were associated with a teratoma. Serotonin production was confirmed in at least 10 cases (five cases in the present study and five cases in previous studies), but carcinoid syndrome was present in only two cases. Three of the 15 cases (20%) showed distant metastases, and the tumors that metastasized were larger than those that did not. These features were almost similar to those observed in the Eur/US series. Three pure carcinoids were also studied for the number of sex chromosomes by fluorescence in situ hybridization (FISH). They did not show a significant numerical abnormality of the X chromosome, which is common in testicular germ cell tumors. Therefore, the genetic background of pure carcinoids might be different from that of common germ cell tumors.

Adult↗

PubMed2003

Mucin expression in nonneoplastic and neoplastic glandular epithelia of the uterine cervix.

Although it is well known that the uterine cervix contains mucin-producing glandular epithelium, only a few studies have described the changes in mucin that accompany malignant transformation. In this study the authors evaluated the characteristics of mucin expression in the normal endocervical epithelium and mucinous and endometrioid adenocarcinomas of the uterine cervix. The normal endocervical epithelium was characterized by predominant sulfomucin and MUC1 expression in all sites and MUC5AC expression in the surface epithelium, while MUC2 was not detected at all and pyloric gland type mucin (using antibody HIK1083) was detected in less than 1% of cases. Cervical adenocarcinomas, especially mucinous adenocarcinomas, showed marked variability in mucin expression that included mucins of pyloric gland and intestinal type.

Adenocarcinoma, Mucinous↗

PubMed2003

Carcinosarcomas (malignant mullerian mixed tumors) of the uterus and ovary: a genetic study with special reference to histogenesis.

The histogenesis of carcinosarcomas (malignant mullerian mixed tumors) of the female genital tract is still not completely understood. In the present study, several different molecular pathologic techniques were applied to determine the histogenesis of 15 uterine and ovarian carcinosarcomas. The patterns of X-chromosome inactivation and the presence of p53 and K-ras mutations were analyzed in the carcinomatous and sarcomatous components. Microsatellite analysis was also performed. Ten tumors were monoclonal, one was biclonal (collision tumor), and another was probably biclonal; the other three were of indeterminate histogenesis. These data indicate that most uterine and ovarian carcinosarcomas are monoclonal.

Adult↗

PubMed2003

Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia.

Silencing of tumor suppressor and tumor-related genes by hypermethylation at promoter CpG islands is frequently found in human tumors, including gastric cancer. Promoter methylation is not restricted to cancer cells, and is also present in non-neoplastic cells as an age-related tissue-specific phenomenon. To clarify the physiological consequence of DAP-kinase and RUNX3 age-related methylation in gastric epithelia, we investigated the promoter methylation status of these genes in both neoplastic and non-neoplastic gastric epithelia obtained at autopsy and surgery, as well as in 10 gastric cancer cell lines. Methylation of DAP-kinase and RUNX3 was detected in 10% (1/10) and 70% (7/10) of the cell lines, respectively, and was almost concordant with their expression status. Among autopsy samples, methylation of these genes was not seen in non-neoplastic gastric epithelia from persons who were aged 22 years and below (0%; 0/4). DAP-kinase was methylated in 87% (13/15) of non-neoplastic gastric epithelia of persons who were aged 45 years or older, while RUNX3 methylation in non-neoplastic gastric epithelia was restricted to individuals who were aged 77 years or older. Among samples obtained from patients with stomach cancer, methylation was observed in both the neoplastic and the corresponding non-neoplastic gastric epithelia; 43% (40/93) and 73% (68/93) for DAP-kinase, and 45% (42/93) and 8% (7/93) for RUNX3, respectively. Frequencies of DAP-kinase and RUNX3 methylation differed significantly in non-neoplastic gastric epithelia (P < 0.01), although those in gastric cancers were almost the same. RUNX3 methylation is mostly cancer-specific, except for very old individuals, and therefore may be a possible molecular diagnostic marker and malignancy predictor.

Adenocarcinoma↗

PubMed2003

Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers.

Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor suppressor and tumor-related genes. To determine the clinicopathological significance of gene promoter methylation in non-small cell lung cancer (NSCLC), we examined the promoter methylation status of the APC, DAP-kinase, E-cadherin, GSTP1, hMLH1, p16, RASSF1A and RUNX3 genes in 75 NSCLCs and corresponding non-neoplastic lung tissues by methylation-specific PCR (MSP). The frequencies of methylation in NSCLCs and corresponding non-neoplastic lung tissues were: 37% (28 of 75) and 48% (36 of 75) for APC, 28% (21 of 75) and 13% (10 of 75) for DAP-kinase, 29% (22 of 75) and 15% (11 of 75) for E-cadherin, 1% (1 of 75) and 0% (0 of 75) for GSTP1, 7% (5 of 75) and 0% (0 of 75) for hMLH1, 31% (23 of 75) and 0% (0 of 75) for p16, 43% (32 of 75) and 4% (3 of 75) for RASSF1A, and 20% (15 of 75) and 3% (2 of 75) for RUNX3, respectively. Methylation of p16 was more frequent in squamous cell carcinomas than in adenocarcinomas (P < 0.05), and was associated with tobacco smoking (P < 0.05). On the contrary, methylation of APC and RUNX3 was more frequent in adenocarcinomas than in squamous cell carcinomas (P < 0.05). Thus, a different set of genes is thought to undergo promoter methylation, which leads to the development of different histologies. In addition, methylation of p16, RASSF1A and RUNX3 was mostly cancer-specific (P < 0.05), and may be utilized as a molecular diagnostic marker of NSCLCs.

Adult↗

PubMed2002

Analysis of genetic and epigenetic alterations of the PTEN gene in gastric cancer.

The PTEN tumor suppressor gene on 10q23.3, responsible for the Cowden and Bannayan-Zonana syndromes, encodes a dual-specificity phosphatase able to dephosphorylate both tyrosine phosphate and serine/threonine phosphate residues. Mutational inactivation of PTEN has been reported in various malignancies, including endometrial cancers, ovarian cancers, and glioblastomas. In this study, we investigated PTEN gene mutations in 10 gastric cancer cell lines and 58 primary gastric cancers by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP). Hypermethylation of promoter region CpG islands, an alternative mechanism of gene inactivation to coding region mutations, was also evaluated by methylation specific PCR (MSP). Only one (1.7%) of the 58 primary tumors carried a somatic 5-bp deletion in intron 7 of PTEN, which did not alter the mRNA sequence, and no mutations were detected in any of the cell lines. Similar levels of PTEN mRNA expression were observed in all cell lines and primary tumors studied by RT-PCR, and PTEN promoter CpG islands remained unmethylated. Therefore, we conclude that PTEN does not participate in gastric carcinogenesis as a tumor suppressor gene.

Adenocarcinoma↗

PubMed2002

Pyloric gland-type tubular adenoma superimposed on intraductal papillary mucinous tumor of the pancreas. Pyloric gland adenoma of the pancreas.

We report a rare case of pyloric gland-type tubular adenoma of the main pancreatic duct. It was a grossly visible polypoid nodule and was composed of closely packed pyloric-type glands. This adenoma was present within an intraductal papillary mucinous adenoma (IPMA). In this IPMA lesion, aggregations of pyloric-type glands were occasionally observed, and most of the cells including ductal lining cells expressed pyloric gland-type mucin. The IPMA of the present case showed more extensive pyloric gland metaplasia or differentiation than commonly noted in IPMAs. We consider this pyloric gland-type tubular adenoma to be derived from a selective growth of IPMA cells showing pyloric gland metaplasia.

Adenoma↗

PubMed2002

Promoter methylation status of E-cadherin, hMLH1, and p16 genes in nonneoplastic gastric epithelia.

Silencing of tumor suppressor and tumor-related genes by hypermethylation at promoter CpG islands is one of the major events in human tumorigenesis. Promoter methylation is also present in nonneoplastic cells as an age-related tissue-specific phenomenon that precedes the development of neoplasia. To clarify the significance of promoter methylation in nonneoplastic gastric epithelia as a precancerous signal, we investigated promoter methylation status of E-cadherin, hMLH1, and p16 genes in nonneoplastic cells of various organs obtained at autopsy, and compared the results with those of nonneoplastic epithelia of a cancerous stomach. Methylation of these genes was not seen in nonneoplastic cells of organs from people who were 22 years and younger (0%, 0 of 6). In contrast, E-cadherin and p16 were methylated in nonneoplastic gastric epithelia of persons who were 45 years or older. The numbers were 86% (12 of 14) and 29% (4 of 14), respectively. E-cadherin methylation occurred preferentially in the intestines, whereas p16 methylation was almost restricted to the stomach. For samples obtained from patients with stomach cancer, methylation was frequently observed in both neoplastic and corresponding nonneoplastic gastric epithelia: 47% (44 of 94) and 67% (63 of 94) for E-cadherin, 32% (30 of 94) and 24% (23 of 94) for hMLH1, and 22% (21 of 94) and 44% (41 of 94) for p16, respectively. hMLH1 methylation was not seen in nonneoplastic gastric epithelia from autopsy samples but occurred significantly in samples from nonneoplastic tissues of individuals with stomach cancer. Therefore, detection of hMLH1 methylation in nonneoplastic gastric epithelia may be useful for screening patients who may be at risk of developing gastric cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2002

E-cadherin expression in follicular carcinoma of the thyroid.

Follicular carcinoma (FC) of the thyroid is distinguished from follicular adenoma (FA) by confirmation of invasion or metastasis. However, it is still unknown how FC acquires the potential for invasion or metastasis. Twenty early FC (pT1 and pT2) were analyzed for immunohistochemical E-cadherin (E-CD) expression. Four of four (100%) widely invasive FC showed reduced E-CD expression, whereas only two of 16 minimally invasive FC showed reduced expression. In most of the minimally invasive FC, both E-CD and beta-catenin were expressed on cell-cell boundaries, even in areas where capsular invasion occurred. These results suggest that the mechanism of invasion may be different between widely invasive FC and minimally invasive FC, and that E-CD is probably responsible for the invasion of widely invasive FC. Analysis of methylation of the E-CD gene promoter using the methylation-specific polymerase chain reaction (MSP) method revealed no methylated alleles in the DNA from FC.

Adenocarcinoma, Follicular↗