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Papers - KANAI Yae

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Collecting duct carcinoma of the kidney presenting uncommon findings.

Maeda T, Tateishi U, Nakagawa T, Ojima H, Kanai Y, Fujimoto H.

Eur J Radiol Extra (Elsevier BV) 49 ( 1 ) 25 - 29 2004

Accepted, ISSN 1571-4675

We present a case of collecting duct carcinoma (CDC) of the kidney exhibiting uncommon radiologie findings. A 67-year-old man had a history of hepatic resection for hepatocellular carcinomas. Follow-up CT revealed a left renal mass that presented an exophytic appearance with distortion of the renal contour. Since malignancy was suspected, the patient underwent a left radical nephrectomy with partial adrenalectomy and para-aortic lymph nodes dissection. Histologically, the majority of the tumor showed a tubular structure, and the rest was a solid area resembling transitional cell carcinoma (TCC). A diagnosis of CDC was made. In previous reports, common radiologie findings of CDC have been a medullary location and infiltrative appearance. Therefore, the outer contour of the affected kidney is usually maintained when the mass is relatively small. However, the present case did not show these common findings. In conclusion, the radiologic findings of CDC may be various and we should consider this tumor in the differential diagnosis of renal tumors. © 2003 Elsevier Ireland Ltd. All rights reserved.

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

Nakanishi Y, Akimoto S, Sato Y, Kanai Y, Sakamoto M, Hirohashi S.

Appl Immunohistochem Mol Morphol (LIPPINCOTT WILLIAMS & WILKINS) 12 ( 4 ) 323 - 328 2004

Accepted, ISSN 15412016

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.

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Laminin 5 β3 and γ2 chains are frequently coexpressed in cancer cells.

Akimoto S, Nakanishi Y, Sakamoto M, Kanai Y, Hirohashi S.

Pathol Int (BLACKWELL PUBLISHING ASIA) 54 ( 9 ) 688 - 692 2004

Accepted, ISSN 13205463

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 gamma 2 chains in 20 cases of squamous cell carcinoma of the tongue and 17 cases of colorectal carcinoma. Laminin 5 beta3 and gamma 2 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 gamma 2 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 gamma 2 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 gamma 2 chain and beta3 chain are both important in the invasiveness of cancer cells.

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Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation.

Sekine S, Takata T, Shibata T, Mori M, Morishita Y, Noguchi M, Uchida T, Kanai Y, Hirohashi, S.

Histopathology (BLACKWELL PUBLISHING LTD) 45 ( 6 ) 573 - 579 2004

Accepted, ISSN 03090167

Aims: Adamantinomatous craniopharyngioma (ACP) resembles histologically some odontogenic tumours, such as ameloblastoma and calcifying odontogenic cyst. However, there has been no evidence that ACP differentiates also functionally as odontogenic epithelium. The aim of this study was to gain evidence of odontogenic epithelial differentiation in ACP by means of immunohistochemistry. Among normal human tissues, enamel proteins are expressed exclusively in teeth, and lymphoid enhancer factor 1 (LEF1), in co-operation with beta-catenin, play an important role in tooth development. The expression of these proteins is therefore indicative of odontogenic epithelial differentiation.
Methods and results: The expression of enamel proteins and LEF1 was examined in 10 adamantinomatous and six papillary craniopharyngiomas. All the ACPs showed a variable degree of enamel protein expression, including amelogenin, enamelin and enamelysin, mainly in ghost cells. LEF1 was also heterogeneously expressed in ACPs; remarkably, its expression pattern was identical to that of nuclear beta-catenin accumulation. In contrast, none of the papillary craniopharyngiomas expressed enamel proteins or LEF1.
Conclusions: These results suggest that ACP consistently shows odontogenic epithelial differentiation. Since ACPs harbour beta-catenin mutation, the inappropriate activation of beta-catenin/LEF1 complex-dependent transcription may play a critical role in ACP tumorigenesis.

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

Shibata T, Kokubu A, Sekine S, Kanai Y, Hirohashi S.

Am J Pathol (AMER SOC INVESTIGATIVE PATHOLOGY, INC) 164 ( 6 ) 2269 - 2278 2004

Accepted, ISSN 00029440

In a search for signalling 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.

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

Shimamura T, Yasuda J, Ino Y, Gotoh M, Tsuchiya A, Nakajima A, Sakamoto M, Kanai Y, Hirohashi S.

Cancer Res (AMER ASSOC CANCER RESEARCH) 64 ( 19 ) 6989 - 6995 2004

ISSN 00085472

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.

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

Nam JS, Ino Y, Kanai Y, Sakamoto M, Hirohashi S.

Clin Exp Metastasis (KLUWER ACADEMIC PUBL) 21 ( 1 ) 49 - 56 2004

Accepted, ISSN 0262-0898

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.

Malignant mixed epithelial and stromal tumours of the kidney: a report of the first two cases with a fatal clinical outcome.

Nakagawa T, Kanai Y, Fujimoto H, Kitamura H, Furukawa H, Maeda S, Oyama T, Takesaki T, Hasegawa T.

Histopathology (BLACKWELL PUBLISHING LTD) 44 ( 3 ) 302 - 304 2004

ISSN 0309-0167

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

Etoh T, Kanai Y, Ushijima S, Nakagawa T, Nakanishi Y, Sasako M, Kitano S, Hirohashi S.

Am J Pathol (AMER SOC INVESTIGATIVE PATHOLOGY, INC) 164 ( 2 ) 689 - 699 2004

Accepted, ISSN 00029440

We evaluated the significance of aberrant DNA methyltransferase I (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 I (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.

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

Ohnishi S., Ohnami S., Laub F., Aoki K., Suzuki K., Kanai Y., Haga K., Asaka M., Ramirez F., Yoshida T.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 308 ( 2 ) 251 - 256 2003.08

ISSN 0006291X

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. © 2003 Elsevier Inc. All rights reserved.

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Cell adhesion system and human cancer morphogenesis.

Hirohashi S. Kanai Y.

Cancer Sci (JAPANESE CANCER ASSOC) 94 ( 7 ) 575 - 581 2003

Accepted, ISSN 00720151

Cell-cell adhesion determines the polarity of cells and participates in the maintenance of the cell societies called tissues. Cell-cell adhesiveness is generally reduced in human cancers. Reduced intercellular adhesiveness allows cancer cells to disobey the social order, resulting in destruction of histological structure, which is the morphological hallmark of malignant tumors. Reduced intercellular adhesiveness is also indispensable for cancer invasion and metastasis. A tumor-suppressor gene product, E-cadherin, and its undercoat proteins, catenins, which connect cadherins to actin filaments, are located at lateral borders, concentrating on adherens junctions, of epithelial cells and establish firm cell-cell adhesion. The E-cadherin cell adhesion system in cancer cells is inactivated by various mechanisms that reflect the morphological and biological characteristics of the tumor. Silencing of the E-cadherin gene by DNA hypermethylation around the promoter region occurs frequently, even in precancerous conditions. In diffuse infiltrating cancers, mutations are found in the genes for E-cadherin and alpha- and beta-catenins. At the invading front of cancers, the E-cadherin cell adhesion system is inactivated by tyrosine phosphorylation of beta-catenin; an oncogene product, c-erbB-2 protein, is found to associate directly with beta-catenin. The E-cadherin cell adhesion system cross-talks with the Wingless/Wnt signaling pathway through beta-catenin, and expression of genes, which participate in cancer morphogenesis, may be regulated in conjunction with the Wingless/Wnt signaling pathway. Dysadherin, a newly identified cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. In conclusion, inactivation of the E-cadherin cell adhesion system by both genetic and epigenetic mechanisms plays a significant role during multistage human carcinogenesis.

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

Kanai Y, Ushijima S, Nakanishi Y, Sakamoto M, Hirohashi S.

Cancer Lett (ELSEVIER SCI IRELAND LTD) 192 ( 1 ) 75 - 82 2003

Accepted, ISSN 03043835

Alteration of DNA methylation is one of the most consistent epigenctic 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. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

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

Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H, Ishii H, Hirohashi S.

Int J Cancer (WILEY-LISS) 105 ( 4 ) 527 - 532 2003

Accepted, ISSN 00207136

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. (C) 2003 Wiley-Liss, Inc.

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

Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, Haga K, Asaka M, Ramirez F, Yoshida T.

Biochem Biophys Res Commun 308 251 - 256 2003

Accepted

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

Sekine S, Sato S, Takata T, Fukuda Y, Ishida T, Kishino M, Shibata T, Kanai Y, Hirohashi S.

Am J Pathol (AMER SOC INVESTIGATIVE PATHOLOGY, INC) 163 ( 5 ) 1707 - 1712 2003

Accepted, ISSN 00029440

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.

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Overexpression of KIT in chromophobe renal cell carcinoma.

Yamazaki K, Sakamoto M, Ohta T, Kanai Y, Ohki M, Hirohashi S.

Oncogene (NATURE PUBLISHING GROUP) 22 ( 6 ) 847 - 852 2003

Accepted, ISSN 09509232

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.

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

Horikawa Y, Sugano K, Shigyo M, Yamamoto H, Nakazono M, Fujimoto H, Kanai Y, Hirohashi S, Kakizoe T, Habuchi T, Kato T.

J Urol (LIPPINCOTT WILLIAMS & WILKINS) 169 ( 4 ) 1541 - 1545 2003

Accepted, ISSN 00225347

Purpose: We elucidated the role of methylation in the promoter region of the CDH1 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 CDH1 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 CDH1 promoter methylation in 23 (47%). Methylation of the CDH1 gene did not correlate with tumor stage (p = 0.2097) but with high grade transitional cell carcinoma (p = 0.0416). CDH1 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 CDH1 gene promoter methylation is strongly associated with bladder transitional cell carcinoma comprising carcinoma in situ.

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

Nakagawa T, Kanai Y, Saito Y, Kitamura T, Kakizoe T, Hirohashi S.

J Urol (LIPPINCOTT WILLIAMS & WILKINS) 170 ( 6 I ) 2463 - 2466 2003

Accepted, ISSN 00225347

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.

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Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis.

Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S.

Proc Natl Acad Sci USA (Proceedings of the National Academy of Sciences of the United States of America) 99 ( 15 ) 10060 - 10065 2002

Accepted, ISSN 00278424

DNA hypomethylation on pericentromeric satellite regions is an early and frequent event associated with heterochromatin instability during human hepatocarcinogenesis. A DNA methyltransferase, DNMT3b, is required for methylation on pericentromeric satellite regions during mouse development. To clarify the molecular mechanism underlying DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis, we examined mutations of the DNMT3b gene and mRNA expression levels of splice variants of DNMT3b in noncancerous liver tissues showing chronic hepatitis and cirrhosis, which are considered to be precancerous conditions, and in hepatocellular carcinomas (HCCs). Mutation of the DNMT3b gene was not found in HCCs. Overexpression of DNMT3b4, a splice variant of DNMT3b lacking conserved methyltransferase motifs IX and X, significantly correlated with DNA hypomethylation on pericentromeric satellite regions in precancerous conditions and HCCs (P = 0.0001). In particular, the ratio of expression of DNMT3b4 to that of DNMT3b3, which is the major splice variant in normal liver tissues and retains conserved methyltransferase motifs I, IV, VI, IX, and X, showed significant correlation with DNA hypomethylation (P = 0.009). Transfection of human epithelial 293 cells with DNMT3b4 cDNA induced DNA demethylation on satellite 2 in pericentromeric heterochromatin DNA. These results suggest that overexpression of DNMT3b4, which may lack DNA methyltransferase activity and compete with DNMT3b3 for targeting to pericentromeric satellite regions, results in DNA hypomethylation on these regions, even in precancerous stages, and plays a critical role in human hepatocarcinogenesis by inducing chromosomal instability.

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Pancreatic metastasis from renal cell carcinoma extending into the main pancreatic duct: a case report.

Yachida S, Fukushima N, Kanai Y, Nimura S, Shimada K, Yamamoto J, Sakamoto M.

Jpn J Clin Oncol (OXFORD UNIV PRESS) 32 ( 8 ) 315 - 317 2002

Accepted, ISSN 03682811

While metastasis to the pancreas is uncommon, it may occur from renal cell carcinomas (RCCs). We here present a case of pancreatic metastasis from RCC extending into the main pancreatic duct (MPD) in a 66-year-old Japanese man. The patient had a history of RCC treated with a radical nephrectomy 17 years previously and was found to have a mass similar to2 cm in diameter in the body of the pancreas on radiological images. The patient was suspected of having pancreatic metastasis from RCC and underwent a distal pancreatectomy with splenectomy. Histologically, the tumor consisted of cells arranged in trabecular and alveolar structures with clear or eosinophilic granular cytoplasm, compatible with a metastatic RCC. The pancreatic tumor extended into the MPD with the stream of pancreatic juice. This condition is similar to RCC extension into the renal vein and the inferior vena cava. In conclusion, although extension into the MPD may be rare, such a growth pattern may be characteristic of metastases from RCCs.

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