Biomedical subjects

Yae Kanai

Publications and source records attributed to Yae Kanai.

At least 37 records · Page 2Linked to original sources

PubMed2005

DNA hypomethylation on pericentromeric satellite regions significantly correlates with loss of heterozygosity on chromosome 9 in urothelial carcinomas.

PURPOSE: DNA methylation has important roles in genomic stability. Accordingly DNA hypomethylation on pericentromeric satellite regions may induce chromosomal instability through heterochromatin decondensation and chromosomal recombination enhancement. We elucidated the significance of aberrant DNA methylation on pericentromeric satellite regions during urothelial carcinogenesis. MATERIALS AND METHODS: We examined DNA methylation status on satellites 2 and 3 by Southern blotting and determined the allelic status of chromosome 9 using 6 microsatellite markers (D9S775, D9S925, D9S304, D9S303, D9S283 and D9S747) in 27 transitional cell carcinomas of the bladder, ureter or renal pelvis and corresponding noncancerous tissues. RESULTS: DNA hypomethylation on satellites 2 and 3 was detected in 2 (7%) and no (0%) noncancerous tissues, and in 11 (41%) and 12 (44%) urothelial carcinomas, respectively. DNA hypomethylation in urothelial carcinomas significantly correlated with histological grade (p = 0.0012 and 0.0043), invasion depth (p = 0.0055 and 0.0228) and morphological structure (papillary vs nodular, p = 0.0161 and 0.0297) for satellites 2 and 3, respectively. Loss of heterozygosity on at least 1 locus of chromosome 9 was detected in 14 urothelial carcinomas (52%). DNA hypomethylation on satellites 2 (p = 0.0098) and 3 (p = 0.0034) significantly correlated with loss of heterozygosity on chromosome 9. CONCLUSIONS: DNA hypomethylation on pericentromeric satellite regions may participate in the development and progression of urothelial carcinomas by inducing loss of heterozygosity on chromosome 9.

Aged↗

PubMed2005

DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis.

PURPOSE: We elucidated the significance of aberrant DNA methylation on multiple CpG islands and its correlation with DNA methyltransferase DNMT1 protein expression during urothelial carcinogenesis. MATERIALS AND METHODS: We examined the DNA methylation status on multiple CpG islands by methylation specific polymerase chain reaction and combined bisulfite restriction enzyme analysis in 12 specimens of normal urothelium, 23 of noncancerous urothelium showing no remarkable histological changes obtained from patients with bladder cancer (NBC) and 70 of transitional cell carcinoma (TCC). RESULTS: DNA methylation on CpG islands of the p16 (0%, 17% and 21%) and death-associated protein kinase (13%, 33% and 29%) genes, and methylated in tumor-2 (56%, 60% and 76%), 12 (0%, 6% and 30%), 25 (25%, 27% and 35%) and 31 (45%, 56% and 79%) clones was detected in normal urothelium, NBCs and TCCs, respectively. The incidence of concurrent DNA hypermethylation on 3 or more CpG islands in NBCs (38%) was significantly higher than that in normal urothelium (0%, p = 0.0455) and even higher in TCCs (59%, p = 0.0043). The incidence of the CpG island methylator phenotype in nonpapillary carcinomas (nodular invasive carcinomas and their precursors, ie flat carcinoma in situ, 71%) was significantly higher than in papillary carcinomas (40%, p = 0.0143). In all specimens examined concurrent DNA hypermethylation on 3 or more CpG islands significantly correlated with immunohistochemically evaluated DNMT1 protein over expression (p = 0.0167). CONCLUSIONS: DNA hypermethylation on multiple CpG islands in association with DNMT1 protein over expression may participate in multistage urothelial carcinogenesis even at the precancerous stage and particularly in the development of nodular invasive carcinomas of the bladder.

Carcinoma, Transitional Cell↗

PubMed2005

Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas.

Aberrant DNA methylation has been shown to play an important role during multistage carcinogenesis in various human organs. The aim of the present study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during pancreatic carcinogenesis. Immunohistochemical analysis of DNMT1 in 48 peripheral pancreatic duct epithelia showing no remarkable histological findings without an inflammatory background (DE), 54 peripheral pancreatic duct epithelia with an inflammatory background (DEI), 188 pancreatic intraepithelial neoplasias (PanIN), and 220 areas of invasive ductal carcinoma from surgical specimens resected from 100 patients, was carried out. The average incidence of DNMT1 immunoreactivity increased progressively from DE to DEI (P = 0.003), from DE and DEI to PanIN (P < 0.0001), among PanIN with different grades of dysplasia (from PanIN I to PanIN II, P = 0.0012), from PanIN to invasive ductal carcinomas (P < 0.0001) and among invasive ductal carcinomas with different grades of histological differentiation (from well or moderately to poorly differentiated adenocarcinomas, P < 0.0001). High-level DNMT1 protein expression in invasive ductal carcinomas was correlated significantly with an advanced t category (P = 0.0224) and an advanced stage (P = 0.0294). Moreover, patients with invasive ductal carcinomas showing high-level DNMT1 protein expression had a poorer outcome (P = 0.0469). These data suggest that increased DNMT1 protein expression participates in multistage pancreatic carcinogenesis from the precancerous stage to malignant progression of ductal carcinomas and may be a biological predictor of poor prognosis.

Adult↗

PubMed2005

Array-based comparative genomic hybridization analysis of high-grade neuroendocrine tumors of the lung.

We examined a large number of primary high-grade neuroendocrine tumors of the lung (10 small cell lung carcinomas and 31 large cell neuroendocrine carcinomas) by using array-based comparative genomic hybridization using microarrays spotted with 800 bacterial artificial chromosome clones containing tumor-related genes from throughout the human genome. We identified the genome-wide copy number alteration profiles of these tumors, including recurrent amplifications located at 2q21.2, 3q21-27, 3q26, 3q27-29, 5p14.2, 5p13, 7q21.1, 8q21, and 8q24 and homozygous deletions at 1p36, 4p16, 4p16.3, 9p21.3, 9p21, 19p13.3, and 20q13. Our results revealed that small cell lung carcinomas and large cell neuroendocrine carcinomas have multiple characteristic chromosomal alterations in common, but that distinctive alterations also exist between the two subtypes. Moreover, we found that the two subtypes undergo different processes of accumulating these genetic alterations during tumor development. By comparing the genetic profiles with the clinicopathological features, we discovered many chromosomal loci whose alterations were significantly associated with clinical stage and patient prognosis. These results will be valuable for evaluating clinical status, including patient prognosis, and for identifying novel molecular targets for effective therapies.

Carcinoma, Small Cell↗

PubMed2004

Dysadherin expression facilitates cell motility and metastatic potential of human pancreatic cancer cells.

Dysadherin is a membrane glycoprotein expressed strongly in several human cancers. Overexpression of dysadherin in tumor cells is closely associated with malignant phenotype (e.g., metastasis) and poor prognosis. In our analysis, six pancreatic cancer cell lines showed a positive correlation between dysadherin expression and cell motility. Introduction of small interfering RNA (siRNA) against dysadherin into the Panc-1 cell line caused reduction of dysadherin expression and suppression of cell motility. In contrast, stable transfection of a dysadherin expression vector into the Capan-1 cell line increased cell motility. In vivo, the metastatic potential of orthotopically transplanted Capan-1 tumor cells in severe combined immunodeficient mice was increased by dysadherin overexpression. Cell morphology and actin organization were also influenced by modulation of dysadherin expression. Cells transfected with dysadherin siRNA tended to have a relatively larger, more spread shape and increased transverse actin stress fibers compared with parent cells and cells transfected with control siRNA. Our study suggests that dysadherin is able to modulate actin structures, stimulate cell motility, and contribute directly to the metastatic potential of human pancreatic cancer cells.

Actins↗

PubMed2004

Alterations in gene expression associated with the overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, during human hepatocarcinogenesis.

PURPOSE: Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, correlates significantly with DNA hypomethylation in pericentromeric satellite regions, which is known to result in centromeric decondensation and enhanced chromosomal recombination in precancerous conditions and hepatocellular carcinomas (HCCs). We aimed to elucidate further the significance of DNMT3b4 during human hepatocarcinogenesis. METHODS: DNMT3b4-transfected human epithelial 293 cells were characterized using growth rate measurements, gene expression microarray, and quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses. RT-PCR was also performed on eight normal liver specimens, 45 noncancerous liver specimens showing chronic hepatitis or cirrhosis, which are considered to be precancerous conditions, and 56 HCCs. RESULTS: The growth rate of the DNMT3b4 transfectants was about double that of mock-transfectants. Induction of signal transducer and activator of transcription 1 (STAT1), an effector of interferon signaling, and of a set of downstream genes implicated in such signaling, was observed in the DNMT3b4 transfectants. There was significant correlation between the mRNA expression levels of DNMT3b4 and STAT1 in HCCs. mRNA expression levels of STAT1 and the three downstream genes examined were all significantly elevated in the chronic hepatitis and cirrhosis specimens compared with the normal liver specimens. Among the HCCs, the mRNA expression levels of STAT1 and the downstream genes were higher in tumors without portal vein involvement than in more malignant HCCs with portal vein involvement. Significant correlations between the mRNA expression levels of STAT1 and each of the downstream genes were observed in the tissue samples. CONCLUSIONS: Overexpression of DNMT3b4 is involved in human hepatocarcinogenesis, even at the precancerous stages, not only by inducing chromosomal instability but also by affecting the expression of specific genes.

Carcinoma, Hepatocellular↗

PubMed2004

Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers.

We evaluated the significance of aberrant DNA methyltransferase 1 (DNMT1) protein expression during gastric carcinogenesis. The protein expression of DNMT1, Muc2, human gastric mucin, E-cadherin, and proliferating cell nuclear antigen was examined immunohistochemically in gastric cancers and corresponding noncancerous mucosae from 134 patients. The DNA methylation status of the CpG islands of the p16, human MutL homologue 1 (hMLH1), E-cadherin, and thrombospondin-1 (THBS-1) genes and the methylated in tumor (MINT)-1, -2, -12, and -31 clones was examined by methylation-specific polymerase chain reaction and combined bisulfite restriction enzyme analysis. Epstein-Barr virus (EBV) infection was detected by in situ hybridization. Nuclear immunoreactivity for DNMT1 was not detected in any of the noncancerous epithelia, except in proliferative zones (positive internal control), but was found in 97 (72%) of the gastric cancers. DNMT1 overexpression correlated significantly with poorer tumor differentiation (P < 0.001), but not with the phenotype (gastric type versus intestinal type) of the cancer cells. It also correlated significantly with DNA hypermethylation of the CpG islands of the hMLH1 (P = 0.024) and THBS-1 genes (P = 0.043), and with the CpG island methylator phenotype in the gastric cancers (P = 0.007). Reduced E-cadherin expression correlated significantly with poorer tumor differentiation (P = 0.002), DNA hypermethylation of the E-cadherin gene (P < 0.001) and DNMT1 overexpression (P = 0.014). DNMT1 overexpression was also associated with EBV infection (a potential etiological factor in gastric carcinogenesis) but not with the proliferative activity of the cancer cells as indicated by the proliferating cell nuclear antigen-labeling index. These results suggest that DNMT1 overexpression may not be just a secondary effect of increased cancer cell proliferative activity, but may be associated with EBV infection and other etiological factors during gastric carcinogenesis. Furthermore, DNMT1 may play a significant role in the development of poorly differentiated gastric cancers by inducing frequent DNA hypermethylation of multiple CpG islands.

Adult↗

PubMed2004

Cytoplasmic p120ctn regulates the invasive phenotypes of E-cadherin-deficient breast cancer.

In a search for signaling molecules that act downstream of E-cadherin inactivation in cancer, we examined the expression and localization of E-cadherin-associated proteins in lobular carcinoma, in which the E-cadherin gene is frequently inactivated, and found that E-cadherin down-regulation correlated with the cytoplasmic localization of p120ctn. Similar cytoplasmic localization of p120ctn and growth factor-induced accumulation of tyrosine-phosphorylated p120ctn in the protrusive domain were observed in E-cadherin-deficient breast cancer cells. Down-regulation of endogenous p120ctn by RNA interference promoted stress fiber formation and induced a flattened morphology with an increase of Rho-GTPase activity; it also reduced the development of membranous protrusions and migratory activity in E-cadherin-deficient breast cancer cells. Inactivation of E-cadherin in cancer cells is associated with the conversion from epithelial to mesenchymal phenotype, which also occurs in physiological conditions such as developmental processes. Cytoplasmic localization of p120ctn accompanied by E-cadherin down-regulation was observed in mesoderm cells that had undergone epithelial-mesenchymal transition during early mouse embryogenesis. Collectively, our results suggest that cytoplasmic p120ctn may contribute to the invasive phenotype of E-cadherin-deficient breast cancer cells.

Base Sequence↗

PubMed2004

5-aza-2'-deoxycytidine restores the E-cadherin system in E-cadherin-silenced cancer cells and reduces cancer metastasis.

Down-regulation of the E-cadherin-mediated cell adhesion system is strongly related to cancer invasion and metastasis. Aberrant CpG hypermethylation in the promoter region of the E-cadherin gene has been shown to be responsible for reduction of E-cadherin expression. The present study was designed to test the hypothesis that the demethylating agent 5-aza-2'-deoxycytidine (AZA) can restore the E-cadherin system and reduce the potential for metastasis. AZA treatment modified the methylation status of the 5' CpG island in the E-cadherin promoter, and induced re-expression of E-cadherin in human cancer cells whose E-cadherin expression had been silenced. The re-expressed E-cadherin was correlated with increased in vitro aggregation and reduced motility. After inoculation of cancer cells (MDA-MB-435S) into the mammary fat pads of mice with severe combined immunodeficiency, the mice were treated for nine consecutive weeks with AZA three times per week i.p. The AZA treatment suppressed both growth of the primary tumor and lung metastasis in comparison with untreated controls, suggesting that the suppression of metastasis may be, at least partly, attributable to restoration of E-cadherin expression. Therefore, inhibition of DNA methylation may be useful for preventing cancer metastasis.

Azacitidine↗

PubMed2004

Prognostic significance of dysadherin expression in tongue cancer: immunohistochemical analysis of 91 cases.

The E-cadherin-mediated cell adhesion system is frequently inactivated by multiple mechanisms and is involved in tumor progression in many types of cancer. Recently we have reported a novel cell membrane glycoprotein, dysadherin, which has an anti-cell-cell adhesion function and downregulates E-cadherin. Expressions of dysadherin and E-cadherin were investigated immunohistochemically in 91 patients with squamous cell carcinoma of the tongue to determine the correlation between the 2 molecules and their associations with the clinicopathologic features of the tumors and with patient survival. Dysadherin was expressed at the cell membranes of many cancer cells. Twenty-five percent of the tumors showed dysadherin immunopositivity in more than 50% of the cancer cells. Sixty-nine percent of the tumors showed reduced E-cadherin immunopositivity. There was an inverse correlation between dysadherin expression and E-cadherin expression (P = 0.0001). Increased dysadherin expression was significantly correlated with an infiltrative type of growth pattern (P = 0.001), high tumor-node-metastasis (TNM) stage (P = 0.024), and poor patient survival (P = 0.003). After adjusting for growth pattern, TNM stage, and other clinicopathologic features, increased dysadherin expression and reduced E-cadherin expression were both significant predictors of poor survival (P = 0.0006). Increased dysadherin expression is a significant indicator of poor prognosis in patients with squamous cell carcinoma of the tongue.

Adult↗

PubMed2004

Laminin 5 beta3 and gamma2 chains are frequently coexpressed in cancer cells.

Laminin 5 plays an important role in cell migration during tumor invasion and tissue remodeling. However, previous studies have not clarified whether laminin 5 beta3 chain is coexpressed with laminin 5 gamma 2 chain in cancer cells. The present immunohistochemical study investigated the distribution of the laminin 5 beta3 and gamma2 chains in 20 cases of squamous cell carcinoma of the tongue and 17 cases of colorectal carcinoma. Laminin 5 beta3 and gamma2 chains were expressed in the cytoplasm of tumor cells. Tumor cells at the cancer-stromal interface and at the invasive front frequently showed immunopositivity for laminin 5 beta3 and gamma2 chains in both squamous cell carcinoma of the tongue and colorectal carcinoma. Furthermore, strong expressions of these two proteins were observed in cancer cells invading in a scattered manner. Laminin 5 beta3 expression correlated significantly with laminin 5 gamma2 expression in 20 cases of squamous cell carcinoma of the tongue (P = 0.0002) and 17 cases of colorectal carcinoma (P < 0.0001). These results suggest that in squamous cell carcinoma of the tongue and colorectal carcinoma, laminin 5 gamma2 chain and beta3 chain are both important in the invasiveness of cancer cells.

Adenocarcinoma↗

PubMed2003

Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer.

Krüppel-like factors (KLFs) are key transcriptional regulators of cell differentiation and proliferation. Among the KLF family, the expression of KLF4 (GKLF) and KLF5 (IKLF) is highly restricted in the epithelial cells of several organs such as the gut and skin, and it has been reported that these epithelial-type KLF genes may be involved in colon carcinogenesis. Recently we found that Klf4 and Klf5 genes were significantly expressed in the developmental bladder epithelium of mice as well. Therefore, in this report we studied the involvement of the KLF4 and KLF5 genes in bladder carcinogenesis. First, we analyzed the expression of KLF4 and KLF5 in a variety of human bladder cancer cell lines and surgical specimens by RNA blot and in situ hybridization analyses. Both genes were highly expressed in the normal bladder epithelium, whereas KLF4, but not KLF5, was frequently downregulated in bladder cancer cell lines and cancer tissues. We then transduced the KLF4 and KLF5 genes into the bladder cancer cell lines using adenoviral vectors to examine the biological activities of the genes on those cells. The transduction of KLF4, but not KLF5, suppressed cell growth and induced apoptosis. Our study suggests that inactivation of KLF4 is one of the frequent steps towards bladder carcinogenesis.

Adenoviridae↗

PubMed2003

Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas.

Alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. DNA methyltransferase (DNMT) 1 is a major enzyme involved in establishing genomic methylation patterns. Most of the studies concerning DNMT1 expression in human cancers have been performed only at the mRNA level. To directly examine DNMT1 protein expression levels during human hepatocarcinogenesis, 16 histologically normal liver tissues, 51 noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis, which are considered to be precancerous conditions, and 53 hepatocellular carcinomas (HCCs) were subjected to immunohistochemic examination. If more than 20% of the cells exhibited nuclear DNMT1 staining, the tissue sample was considered to be DNMT1-positive. DNMT1 immunoreactivity was observed in 23 (43%) of the HCCs, but in none (0%) of the histologically normal liver or noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis. The incidence of increased DNMT1 protein expression in HCCs correlated significantly with poor tumor differentiation (p = 0.0006) and portal vein involvement (p = 0.0002). Moreover, the recurrence-free (p = 0.0001) and overall (p < 0.0001) survival rates of patients with HCCs exhibiting increased DNMT1 protein expression were significantly lower than those of patients with HCCs that did not exhibit increased expression. Increased DNMT1 protein expression may play a critical role in the malignant progression of HCCs and be a biologic predictor of both HCC recurrence and a poor prognosis in HCC patients.

Carcinoma, Hepatocellular↗

PubMed2003

Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers.

Alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. DNA methyltransferase (DNMT) 1 is a major enzyme that determines genomic methylation patterns. In order to understand the significance of mutations of the DNMT1 gene during human carcinogenesis, we performed polymerase chain reaction-single strand conformation polymorphism analysis using 46 oligonucleotide primer sets for all 40 coding exons and the 5'-flanking region (450 bp) of the DNMT1 gene in 29 colorectal cancers, 32 stomach cancers, 40 hepatocellular carcinomas (HCCs) and a corresponding sample of non-cancerous tissue from each case. Mutations in coding exons of the DNMT1 gene were detected in two (7%) of the colorectal cancers: they consisted of one-base deletion resulting in deletion of the whole catalytic domain and a point mutation resulting in a single amino acid substitution. No stomach cancers or HCCs showed mutations in the coding exons of the DNMT1 gene. No mutation in the 5'-flanking region of the DNMT1 gene was detected in any of the colorectal and stomach cancers or HCCs. These data suggest that mutational inactivation of the DNMT1 gene that potentially causes a genome-wide alteration of DNA methylation status may be a rare event during human carcinogenesis.

Aged↗

PubMed2003

Overexpression of KIT in chromophobe renal cell carcinoma.

We analysed gene-expression profiles in 15 surgical specimens of conventional, papillary, and chromophobe renal cell carcinomas (RCCs) using high-density oligonucleotide arrays. From about 12,000 genes targeted by the array, 67 were upregulated specifically in each histological type of RCC. The oncogene KIT was one of the genes whose expression was upregulated specifically in chromophobe RCCs. Immunohistochemical analysis demonstrated the KIT gene product on the cell membrane of chromophobe RCC in all cases, although it was not detected in conventional RCCs or non-neoplastic kidneys except for weak staining in the cytoplasm of renal tubules. These results suggest that each histological subtype of RCC has a unique gene-expression profile, and in particular indicates for the first time that KIT could be a useful marker for chromophobe RCC. As overexpression of KIT might be involved in tumor growth, KIT could be a new therapeutic target in this special type of RCC.

Biomarkers, Tumor↗

PubMed2003

Beta-catenin mutations are frequent in calcifying odontogenic cysts, but rare in ameloblastomas.

We have reported previously that alterations to beta-catenin occur frequently in adamantinomatous craniopharyngioma. Based on its histological resemblance to some odontogenic tumors, we suspected the presence of common genetic alterations among these tumors. To address this issue, 11 cases of calcifying odontogenic cyst (COC) and 20 cases of ameloblastoma were investigated for the presence of beta-catenin mutations and beta-catenin expression. Ten COCs were successfully analyzed by direct sequencing, and nine of them were found to harbor somatic beta-catenin mutations. Immunohistochemically, all of the COCs showed nuclear and cytoplasmic expression of beta-catenin with a heterogeneous pattern. No beta-catenin mutations were found in ameloblastomas, except for one case of the follicular type. All follicular ameloblastomas exhibited moderate nuclear and cytoplasmic accumulation of beta-catenin, in contrast to the predominantly membranous expression seen in the plexiform type. beta-Catenin mutation is considered to be a characteristic genetic feature of COC, and may play a critical role in its histogenesis. Although ameloblastoma closely resembles COC histologically, the two have genetically distinctive features.

Adolescent↗

PubMed2003

Hypermethylation of an E-cadherin (CDH1) promoter region in high grade transitional cell carcinoma of the bladder comprising carcinoma in situ.

PURPOSE: We elucidated the role of methylation in the promoter region of the 1 gene in bladder carcinogenesis, particularly in those comprising carcinoma in situ. MATERIALS AND METHODS: A total of 49 cases of transitional cell carcinoma of the bladder obtained from transurethral resection were examined. Methylation status of the 1 promoter region was analyzed by methylation specific polymerase chain reaction from chemically modified DNA after Na-bisulfite treatment. Loss of heterozygosity on 16q was examined by blunt end single strand DNA conformation polymorphism using 4 tetranucleotide repeat microsatellite markers assigned on 16q13 to 22.1. E-cadherin expression was evaluated by immunostaining on formalin fixed, paraffin embedded tissue sections using anti E-cadherin murine monoclonal antibody, HECD1 and standard avidin-biotin immunoperoxidase complex technique. RESULTS: Analysis of the 49 bladder transitional cell carcinoma samples showed 1 promoter methylation in 23 (47%). Methylation of the 1 gene did not correlate with tumor stage (p = 0.2097) but with high grade transitional cell carcinoma (p = 0.0416). 1 promoter methylation was observed at a significantly higher frequency in the carcinoma in situ positive group than in the carcinoma in situ negative group (16 of 18 cases or 89% versus 7 of 31 or 23%, p <0.0001) and it strongly correlated with abnormal E-cadherin expression (p <0.0001). We found 16q loss of heterozygosity in 16 of 47 cases (34%), which correlated with higher histological grade (p = 0.0069) but not with the presence of the carcinoma in situ component (p = 0.1235). CONCLUSIONS: This study showed that 1 gene promoter methylation is strongly associated with bladder transitional cell carcinoma comprising carcinoma in situ.

Alleles↗

PubMed2003

Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder.

PURPOSE: DNA methylation is a key regulator of gene transcription and genomic stability, and alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. We elucidated the significance of aberrant protein expression of DNA methyltransferase (DNMT) 1, a major enzyme involved in the determination of genomic methylation patterns, during human urothelial carcinogenesis. MATERIALS AND METHODS: A total of 61 samples of normal urothelium, 89 noncancerous urothelium samples showing no remarkable histological changes from patients with bladder cancer (NBCs), 78 dysplastic urothelium samples and 174 transitional cell carcinoma samples (TCCs) were subjected to immunohistochemical analysis for DNMT1. RESULTS: The incidence of nuclear DNMT1 immunoreactivity in NBCs (65%) was significantly higher than in normal urothelium (20%, p <0.0001) and the incidence was even higher in dysplastic urothelium samples (84%, p = 0.0017). The incidence of nuclear DNMT1 immunoreactivity was 87% in TCCs and the intensity of nuclear immunoreactivity was markedly increased in TCCs compared with that in dysplastic urothelium samples. DNMT1 expression levels had already increased in NBCs in which the proliferating cell nuclear antigen labeling index had not yet increased. Increased DNMT1 protein expression correlated significantly with histological grade (p <0.0001). DNMT1 protein expression was higher in nonpapillary tumors (p = 0.0001), especially flat carcinoma in situ, than in papillary tumors. CONCLUSIONS: Progressively increasing expression of DNMT1 protein is not entirely a secondary result of increased cell proliferative activity, but rather it is associated with urothelial carcinogenesis even during the precancerous stages. In particular, it is associated with the development of flat carcinoma in situ, which is considered to be a precursor of nodular invasive carcinoma of the bladder.

Adult↗