Details of a Researcher

Papers - KANAI Yae

Division display 361 - 380 of about 439 ／ All the affair displays >>

Correlation of DNA hypomethylation at pericentromeric heterochromatin regions of chromosomes 16 and 1 with histological features and chromosomal abnormalities of human breast carcinomas.

Tsuda H, Takarabe T, Kanai Y, Fukutomi T, Hirohashi S.

Am J Pathol (AMER SOC INVESTIGATIVE PATHOLOGY, INC) 161 ( 3 ) 859 - 866 2002

Accepted, ISSN 00029440

Changes in DNA methylation status are not only important for regulating gene expression but are also suggested to induce chromosome instability. To reveal the correlation of DNA methylation status in heterochromatin regions with tumor histology and with chromosome alterations, DNA methylation status was examined by Southern blot analysis, and numerical and structural chromosome alterations, including the formation of der(16)t(1;16)/der(1;16), were examined by fluorescence in situ hybridization at the two loci in the pericentromeric satellite 2 regions of chromosomes 16 and 1 in 39 human breast carcinomas. DNA hypomethylation at the D16Z3 and the D1Z1 loci was detected in 31% (12 of 39) and 36% (12 of 33) of carcinomas, respectively, and mostly concurred. DNA hypomethylation was more frequent in the carcinoma group of more aggressive histological types or grade 3 than in the carcinoma of less aggressive histological types or grades 1 and 2, and tended to be more frequent in carcinomas with greater than or equal to4 copies of chromosomes 16 and/or 1 than in carcinomas with less than or equal to3 copies of any of these chromosomes. The frequency of DNA hypomethylation at the D16Z3 and the D1Z1 loci was 45% (10 of 22) and 53% (9 of 17) in carcinomas without der(16)t(1;16)/der(1;16), formation, but only 12% (2 of 17) and 19% (3 of 16) in carcinoma with der(16)t(1;16)/der(1;16), respectively (P = 0.036 and 0.070). The 16q breakage was almost equally detected between carcinoma groups with and without the DNA hypomethylation. DNA hypomethylation in the satellite 2 regions was suggested to be associated with the accumulation of a large number of numerical chromosome alterations and involved in the development of breast carcinomas of aggressive histological features. on the contrary, chromosome instability induced by mechanisms other than DNA hypomethylation in heterochromatin regions might cause the formation of der(16)t(1;16)/der(1;16) and less aggressive breast carcinomas.

Access to Document (DOI)

DNA methylation

Kanai Y

Nippon rinsho. Japanese journal of clinical medicine (Nippon rinsho. Japanese journal of clinical medicine) 59 Suppl 6 142 - 146 2001.10

ISSN 00471852

DNA methyltransferase expression and DNA methylation of CpG islands and peri-centromeric satellite regions in human colorectal and stomach cancers.

Kanai Y, Ushijima S, Kondo Y, Nakanishi Y, Hirohashi, S.

Int J Cancer (International Journal of Cancer) 91 ( 2 ) 205 - 212 2001

Accepted, ISSN 00207136

We evaluated the significance of aberrant DNA methyltransferase expression in human carcinogenesis by examining 32 colorectal and 34 stomach cancers. Levels of mRNAs encoding DNA methyltransferases were measured by reverse transcription, followed by real-time quantitative detection of PCR products. The DNA methylation state of CpG islands and peri-centromeric satellite regions was examined by bisulfite modification and Southern blotting, respectively. The average level of mRNA for DNMTI and DNMT3b in colorectal and stomach cancers was significantly higher than in corresponding non-cancerous mucosae, whereas the average level of mRNA for DNMT2 was significantly lower in colorectal and stomach cancers than in non-cancerous tissue. Over-expression of DNMT3b in stomach cancer was significantly higher in cases with lymph node metastasis than in cases without. DNA hypermethylation on the p16, human Mut L homologue-1 and thrombospondin-1 genes and the methylated in tumor (MINT) 1, 2, 12, 25 and 31 clones was found in 23%, 27%, 9%, 23%, 20%, 23%, 20% and 10% of the colon cancers and in 9%, 19%, 30%, 25%, 34%, 19%, 81% and 3% of the stomach cancers, respectively. Criteria for identification of the CpG island methylator phenotype (CIMP) were met in 23% of colorectal cancers and 31% of stomach cancers. DNA hypomethylation on satellites 2 and 3 was detected in 0% and 8% of colorectal and stomach cancers, respectively. Over-expression of DNMTI mRNA was significantly associated with CIMP, whereas the level of DNMT3b mRNA was not associated with CIMP or DNA hypomethylation of pericentromeric satellite regions. These data suggest that both over-expression of the maintenance DNA methyltransferase DNMTI and over-expression of a newly identified de novo DNA methyltransferase, DNMT3b, are involved in human carcinogenesis, probably at different stages and through different mechanisms. © 2001 Wiley-Liss, Inc.

Access to Document (DOI)

Intraductal papillary components in invasive ductal carcinoma of the pancreas are associated with long-term survival of patients.

Fukushima N, Sakamoto M, Mukai K, Kanai Y, Shimada K, Kosuge T, Hirohashi S.

Hum Pathol (W B SAUNDERS CO) 32 ( 8 ) 834 - 841 2001

Accepted, ISSN 00468177

Most patients with pancreatic ductal carcinoma have a poor prognosis. However, in certain cases, 5-year survival can be achieved after surgical resection. Analysis of the pathologic findings associated with good survival rates will assist in identifying the optimum treatment. The clinicopathologic features of 67 patients who underwent surgical resection of ductal adenocarcinoma of the pancreas between 1990 and 1996 were reviewed and correlated with survival rates. There were 42 men and 25 women, with a mean age of 62.1 years (range, 44 to 82 years). The mean greatest diameter of the tumor was 4.3 cm (range, 1.5 to 11 cm). Nineteen patients (29.4%) survived more than 3 years, and 9 (13.2%) survived more than 5 years after surgical resection. The intraductal papillary component (IDPC) of the carcinoma was the main focus of the pathologic observations. IDPC was defined as intraductal papillary proliferative lesions seen in the tumor nodule with proliferative cells consistent with carcinomatous cellular atypia. IDPC was clearly present (++) in 24 patients and vaguely present (+) in 9 patients. Using the Mantel-Cox test, a statistically significant correlation was found between the presence of IDPC (either + or ++) and postoperative patient survival (P = .002). IDPC is a morphologic feature associated with longer patient survival and should be taken into consideration in assessing the pathway of tumor progression. HUM PATHOL 32;834-841. (C) 2001 by W.B. Saunders Company.

Access to Document (DOI)

Expression of cadherins and their undercoat proteins (α-, β-, and γ-catenins and p120) and accumulation of β-catenin with no gene mutations in synovial sarcoma.

Sato H, Hasegawa T, Kanai Y, Tsutsumi Y, Osamura Y, Abe Y, Sakai H, Hirohashi S.

Virchows Arch (Virchows Archiv) 438 ( 1 ) 23 - 30 2001

Accepted, ISSN 09456317

E-cadherin, the major intercellular adhesion molecule of epithelial cells, is important in determining the architecture of sarcomas, especially those showing epithelioid features. In addition to its role in cell adhesion, β-catenin, a cadherin undercoat protein, has been shown to function as a downstream transcriptional activator of the Wnt/Wingless signaling pathway. In order to evaluate the significance of the cadherin cell adhesion system and the Wnt/Wingless signaling pathway in the morphogenesis and/or tumorigenesis of synovial sarcoma (a major type of sarcoma with epithelioid features), immunoreactivity for pan-cadherin, E-cadherin, and their undercoat proteins (α-, β-, and γ-catenins and p120) was evaluated in 15 synovial sarcomas. Immunoreactivity for pan-cadherin, E-cadherin, α-catenin, β-catenin, and p120 was observed in all 15 specimens. Immunoreactivity for pan-cadherin was stronger than that for E-cadherin. Expression of γ-catenin was detected in ten specimens. Although β-catenin was observed only at the cell-cell boundaries in four specimens, it was present in the nucleus and cytoplasm and at the cell-cell boundaries in the other 11, suggesting constitutional activation of the Wnt/Wingless signaling pathway in synovial sarcoma. Direct sequencing for exon 3 of the β-catenin gene, however, revealed no mutations in any of the 15 specimens. In conclusion, other types of cadherin besides E-cadherin, together with cadherin undercoat proteins, may play a role in cell adhesion in synovial sarcoma. Furthermore, mechanisms other than mutation of exon 3 of the β-catenin gene may activate the Wnt/Wingless signaling pathway in this type of tumor.

Access to Document (DOI)

Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis.

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

Hepatology (W B SAUNDERS CO) 33 ( 3 ) 561 - 568 2001

Accepted, ISSN 02709139

To evaluate the significance of alterations in DNA methylation during human hepatocarcinogenesis, we examined levels of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and the DNA methylation status in 67 hepatocellular carcinomas (HCCs), The average level of mRNA for DNMT1 and DNMT3a was significantly higher in noncancerous liver tissues showing chronic hepatitis or cirrhosis than in histologically normal liver tissues, and was even higher in HCCs. Significant overexpression of DNMT3b and reduced expression of DNMT2 were observed in HCCs compared with the corresponding noncancerous liver tissues. DNA hypermethylation on CpG islands of the p16 (8% and 66%) and hMLH1 (0% and 0%) genes and methylated in tumor (MINT) 1 (6% and 34%), 2 (24% and 58%), 12 (21% and 33%), 25 (0% and 5%), and 31 (0% and 23%) clones, and DNA hypomethylation on satellites 2 and 3 (18% and 67%), were detected in noncancerous liver tissues and HCCs, respectively. There was no significant correlation between the expression level of any DNA methyltransferase and DNA methylation status. Reduced expression of DNA repair protein, MBD4, was significantly correlated with poorer tumor differentiation and involvement of portal vein. Slightly reduced expression of MBD2 was detected in HCCs, and the expression of MeCP2 was particularly reduced in HCCs with portal vein involvement. These data suggest that overexpression of DNMT1 and DNMT3a, DNA hypermethylation on CpG islands, and DNA hypomethylation on pericentromeric satellite regions are early events during hepatocarcinogenesis, and that reduced expression of MBD4 may play a role in malignant progression of HCC.

Access to Document (DOI)

mRNA expression of genes altered by 5-azacytidine treatment in cancer cell lines is associated with clinicopathological parameters of human cancers.

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

J Cancer Res Clin Oncol (SPRINGER-VERLAG) 127 ( 12 ) 697 - 706 2001

Accepted, ISSN 01715216

Objective: We attempted to identify tumor-related genes whose expression is affected by DNA methylation and that participate in the determination of the biological characteristics of human cancers. Methods and materials: We used the differential display method in ten 5-azacytidine-treated human cancer cell lines. Time-dependent induction of mRNA expression of Wip1. TROP2, B4-2 protein, BRCA-2 region transcription unit CG005, cofilin, ROCK, CD44, and interferon-inducible protein 6-16 was observed during 5-azacytidine treatment. We then evaluated the mRNA expression of these genes in 26 stomach and 32 colorectal cancers and 44 hepatocellular carcinomas (HCCs) and in the corresponding non-cancerous tissues. Results Significantly reduced rn RNA expression of Wip1, B4-2, and cofilin in stomach cancers, of Wip1, B4-2, BRCA-2 region transcription unit CG005, cofilin, and ROCK in colorectal cancers, and of TROP2, B4-2, and BRCA-2 region transcription unit CG005 in HCCs, was observed in comparison with the corresponding non-cancerous tissues, whereas overexpression of TROP2 was detected in colorectal cancers. Reduced expression of Wip1 and BRCA-2 region transcription unit CG005 was significantly correlated with poorer differentiation of HCCs, and mRNA expression of these genes was significantly reduced in HCCs associated with portal vein involvement compared with HCCs without such involvement. Expression of TROP2 mRNA was significantly higher in chronically diseased liver from HCC patients compared with histologically normal liver, but was reduced in progressed HCCs. Reduced expression of B4-2 protein was observed in association with hepatitis B virus infection of HCC patients. Conclusions: These data suggest that DNA methylation may play a role in human multistage carcinogenesis through direct or indirect regulation of multiple tumor-related genes.

Access to Document (DOI)

Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis.

Kanai Y, Ushijima S, Tsuda H, Sakamoto M, Hirohashi S.

Cancer Lett (Cancer Letters) 148 ( 1 ) 73 - 80 2000

Accepted, ISSN 03043835

The aim of this study was to examine the significance of aberrant DNA methylation, the participation of which in genetic instability is controversial, in hepatocarcinogenesis. The DNA methylation status of the region around the promoter of the E-cadherin tumor suppresser gene, which is located on 16q22.1, and the allelic status at the D16S421 locus, which is adjacent to the E-cadherin locus, were examined using microdissected liver specimens from 38 hepatocellular carcinoma (HCC) patients. Almost all of the non-cancerous liver tissues showed histological findings compatible with chronic hepatitis and cirrhosis, which are considered to be precancerous conditions. DNA hypermethylation was detected in 61% of the non-cancerous liver tissues. The incidence of DNA hypermethylation in the non-cancerous liver tissues of patients with HCCs also showing DNA hypermethylation (72%) was significantly higher than that of patients without DNA hypermethylation in their HCCs (53%, P<0.05). Loss of heterozygosity (LOH) at the D16S421 locus was detected in 35% of the non-cancerous liver tissues. The incidence of LOH in the non-cancerous liver tissues of patients with HCCs also showing LOH was 78%, whereas LOH was not detected in non-cancerous liver tissues of patients without LOH in their HCCs. Fifty-two percent of the non-cancerous liver tissues showed both or neither of DNA hypermethylation and LOH; the incidence of DNA hypermethylation alone in non-cancerous liver tissue was 41%. The incidence of LOH alone in non-cancerous liver tissue (7%) was significantly lower compared to those of the former two cases (P<0.0001). These data suggest that aberrant DNA methylation participates in the precancerous stage of hepatocarcinogenesis by preceding, or causing, LOH. Copyright (C) 2000 Elsevier Science Ireland Ltd.

Access to Document (DOI)

GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas.

Tchou JC, Lin X, Freije D, Isaacs WB, Brooks JD, Rashid A, De Marzo AM, Kanai Y, Hirohashi S, Nelson WG.

Int J Oncol 16 663 - 676 2000

Accepted

Signet-ring cell carcinoma of the urinary bladder associated with transitional cell carcinoma of the right ureter.

Kume H, Kanai Y, Tobisu K, Fujimoto H, Tomita K, Kakizoe T.

Scand J Urol Nephrol 34 278 - 279 2000

Accepted

Multistep carcinogenesis and DNA methylation.

Hirohashi S, Kanai Y.

Princess Takamatsu Symp 31 5 - 10 2000

Aberrant expression of β-catenin and mutation of exon 3 of the β-catenin gene in renal and urothelial carcinomas.

Zhu X, Kanai Y, Saito A, Kondo Y, Hirohashi S.

Pathol Int (Pathology International) 50 ( 12 ) 945 - 952 2000

Accepted, ISSN 13205463

The present study attempted to clarify the significance of aberrant expression of β-catenin protein and mutation of exon 3 of the β-catenin gene in renal and urothelial carcinogenesis. β-Catenin expression was examined immunohistochemically and mutation of the β-catenin gene was analyzed by polymerase chain reaction-single strand conformation polymorphism (SSCP) and direct sequencing. β-Catenin immunoreactivity was observed at the cell membrane in all 30 renal cell carcinomas (RCC) examined, and no RCC showed a mobility-shifted SSCP band. Of 46 transitional cell carcinomas (TCC) examined, there was reduced expression of β-catenin, as compared with its expression in non-cancerous transitional epithelium, in 22 cases (48%) and catenin accumulation in the nucleus in five cases (11%). Of four renal pelvis TCC examined, point mutation of exon 3 of the β-catenin gene at codon 45 resulting in amino acid substitution (Ser to Phe) was detected in one (25%). The incidence of reduced expression of β-catenin correlated significantly with the growth pattern (superficial type vs invasive type) of TCC (P < 0.05). These data indicate that: (1) aberrant β-catenin expression may be at least partly involved in urothelial carcinogenesis, but less significantly so in renal carcinogenesis, and (2) it may be associated with the progression of TCC showing invasive growth.

Access to Document (DOI)

Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis--A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from ---

Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S.

Hepatology 32 970 - 979 2000

Accepted

Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis - A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma

Kondo Y., Kanai Y., Sakamoto M., Mizokami M., Ueda R., Hirohashi S.

Hepatology (Hepatology) 32 ( 5 ) 970 - 979 2000

ISSN 02709139

A study was conducted to examine the significance of genetic instability and aberrant DNA methylation during hepatocarcinogenesis. Genomic DNA was extracted from 196 microdissected specimens of noncancerous liver tissue that showed no marked histologic findings or findings compatible with chronic hepatitis or cirrhosis, and 80 corresponding microdissected specimens of hepatocellular carcinoma (HCC) from 40 patients. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were examined by polymerase chain reaction (PCR) using 39 microsatellite markers, and DNA methylation status on 8 CpG islands was examined by bisulfite-PCR. In noncancerous liver tissues, LOH, MSI, and DNA hypermethylation were found in 15 (38%), 6 (15%), and 33 (83%) of 40 cases, respectively. The incidence of DNA hypermethylation in histologically normal liver was similar to that in chronic hepatitis and cirrhosis, although neither LOH nor MSI was found in histologically normal liver. In cancerous tissues, LOH, MSI, and DNA hypermethylation were found in 39 (98%), 8 (20%), and 40 (100%) of 40 cases, respectively. CpG islands of the p16 gene and methylated in tumor 1, 2, 12, and 31 clones were frequently methylated in cancerous tissues, although neither the thrombospondin-1 nor the human Mut L homologue (hMLH1) gene was methylated. Absence of silencing of the hMLH1 gene by DNA hypermethylation is consistent with the low incidence of MSI in HCCs. The results of this study indicate that LOH and aberrant DNA methylation contribute to hepatocarcinogenesis; DNA hypermethylation in particular, which precedes or may even cause LOH, is as an early event during hepatocarcinogenesis.

Access to Document (DOI)

Resection of liver metastases after pancreatoduodenectomy: Report of seven cases

Fujii K., Yamamoto J., Shimada K., Kosuge T., Yamasaki S., Kanai Y.

Hepato-Gastroenterology (Hepato-Gastroenterology) 46 ( 28 ) 2429 - 2433 1999.10

ISSN 01726390

There has been no English report of a long survivor after hepatectomy for metastasis from peri-ampullary malignancies, who had previously undergone pancreatoduodenectomy (PD) for primary disease. Herein, we report 7 patients of liver metastases who underwent 8 hepatectomies after PD for peri-ampullary malignancies. One patient whose liver metastasis was neuroendocrine tumor, survived 2 years and 6 months without recurrence after hepatectomy. Another patient who had 2 hepatectomies for metastasis from duodenal leiomyosarcoma survived for 3 years and 20 days after the first hepatectomy. Procedure of hepatectomy comprised 4 limited resections (including 1 second hepatectomy) and 4 lobectomies at the first resection. Hepatic inflow clamp was used in 6 out of 8 hepatectomies and 4 out of 8 hepatectomies did not require allogeneic blood transfusion. Bacterial contamination of the drained discharge from the cut surface of the liver, mostly representative of enteric organisms, was identified in all but 2 patients who were not examined. Subphrenic abscesses developed in 2 patients after removal of the drains. Thus, prophylactic use of abdominal drain is indispensable after hepatectomy for the patients with bilioenteric anastomosis.

Disruption of E-cadherin-mediated cell adhesion systems in gastric cancers in young patients.

Saito A, Kanai Y, Maesawa C, Ochiai A, Torii A, Hirohashi S.

Jpn J Cancer Res (Japanese Journal of Cancer Research) 90 ( 9 ) 993 - 999 1999

Accepted, ISSN 09105050

The aim of this study was to elucidate the pathogenetic backgrounds of early-onset gastric cancers. Mutations of the E-cadherin and β-catenin genes were analyzed by subjecting microdissected cancer cells and corresponding non-cancerous epithelial cells obtained from 9 gastric cancer patients under 35 years old to polymerase chain reaction-single strand conformation polymorphism analysis. Somatic, but no germline, E-cadherin gene mutations were detected in 6 (67%) of the patients. The cancer cells of 2 patients were exon 9-deleted E-cadherin molecule-immunoreactive. Neither somatic nor germline mutations in exon 3 of the β-catenin gene were observed in any patient. One patient lacked β-catenin immunoreactivity and the cancer cells of 6 others showed cytoplasmic β-catenin immunoreactivity. The E-cadherin-mediated cell adhesion system in the cancer cells of all the patients examined appeared to be disrupted, indicating that somatically acquired dysfunction of this system plays an important role in early-onset diffuse-type gastric cancers. Helicobacter pylori infection was observed in 6 (67%) of our 9 patients, an incidence higher than the average in young Japanese individuals. Thus, early-onset gastric cancers may be attributabIe to environmental factors such as Helicobacter pylori infection.

Access to Document (DOI)

Reduced mRNA expression of the DNA demethylase, MBD2, in human colorectal and stomach cancers.

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

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications) 264 ( 3 ) 962 - 966 1999

Accepted, ISSN 0006291X

A study was performed to evaluate the significance of aberrations of the newly identified DNA demethylase, MBD2, in human carcinogenesis. Levels of expression of DNA demethylase mRNA were examined by reverse transcription followed by real-time quantitative detection of the PCR products in 32 samples of colorectal cancer tissue, 24 stomach cancers, and the corresponding noncancerous mucosae. DNA demethylase mRNA levels normalized with glyceraldehyde-phosphate dehydrogenase (GAPDH) mRNA were reduced in 31 (97%) of the 32 colorectal cancers and in 22 (92%) of the 24 stomach cancers when compared with the levels in the corresponding noncancerous mucosae. The average levels of DNA demethylase mRNA expression normalized with GAPDH mRNA in each of the colorectal (0.81 ± 0.55) and stomach (2.88 ± 0.23) cancers were significantly lower than in the noncancerous mucosae (1.90 ± 0.16 and 5.11 ± 0.34, respectively, p < 0.0001). There was no significant association between the DNA demethylase mRNA level and malignant potential in both colorectal and stomach cancers. These data suggest that reduced expression of DNA demethylase may play a role at a certain step of multistage carcinogenesis. Reduction of DNA demethylase mRNA expression may be, if anything, one of the early events of carcinogenesis, but may not participate in the malignant progression of tumors.

Access to Document (DOI)

DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis.

Kanai Y, Hui AM, Sun L, Ushijima S, Sakamoto M, Tsuda H, Hirohashi S.

Hepatology (Hepatology) 29 ( 3 ) 703 - 709 1999

Accepted, ISSN 02709139

To examine the significance of aberrant DNA methylation in hepatocarcinogenesis, the DNA methylation status at the D17S5 locus and mRNA expression of a candidate tumor suppressor gene, HIC-1 (hypermethylated-in- cancer), which was identified at the D17S5 locus, in primary hepatocellular carcinomas (HCCs) and their corresponding noncancerous liver tissues were assessed. DNA hypermethylation at the D17S5 locus was detected in 44% of the noncancerous liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, but was not observed in noncancerous liver tissues showing no remarkable histological findings. The incidence of DNA hypermethylation at this locus was significantly higher in HCCs (90%) than noncancerous liver tissues (P < .001). Loss of heterozygosity at the D17S5 locus, which was preceded by DNA hypermethylation at the same locus, was detected in 54% of HCCs. The HIC-1 mRNA expression level of noncancerous liver tissues showing chronic hepatitis or cirrhosis was significantly lower than that of noncancerous liver tissues showing no remarkable histological findings (P < .01), and that of HCCs was even lower than that of noncancerous liver tissues (P < .05). Poorly differentiated HCCs showed lower expression levels than well- to moderately differentiated HCCs. Mutation of the p53 gene may be involved in HIC-1 inactivation. Moreover, wild-type p53 did not overcome DNA hypermethylation at the D17S5 locus to activate HIC-1 in HCCs. These data suggest that aberrant DNA methylation at this locus and reduced HIC-1 mRNA expression participate in hepatocarcinogenesis during both early developmental stages and malignant progression of HCCs.

Access to Document (DOI)

Reduction of integrin β4 and enhanced migration on laminin in association with intraepithelial spreading of urinary bladder carcinomas.

Harabayashi T, Kanai Y, Yamada T, Sakamoto M, Ochiai A, Kakizoe T, Koyanagi T, Hirohashi S.

J Urol (Journal of Urology) 161 ( 4 ) 1364 - 1371 1999

Accepted, ISSN 00225347

Purpose: The aim of the present study was to investigate the biological and molecular basis of intraepithelial spreading (IES) of carcinomas in situ (CIS) of the urinary bladder, which were considered to be precursors of nodular invasive carcinomas. Materials and Methods: The propensity for IES of human transitional carcinoma cells was examined by inoculation into murine renal pelvis and urinary bladder, and the biological character of the cells with a high propensity for IES was explored in vitro. Results: Three of 6 cell lines exhibited a high propensity for IES. When cultured on laminin, these IES cells scattered, whereas 3 non-IES cells and 2 immortalized transitional epithelial cells did not. IES cells showed strong adhesiveness, haptotaxis and enhanced migration on laminin compared with both non-IES and immortalized transitional epithelial cells. In IES cells, expression of the integrin β4 subunit was markedly reduced and the integrin α6β1 complex was predominant compared with the integrin α6β4 complex. Transfection of IES cells with integrin β4 subunit cDNA inhibited their ability to migrate on laminin and their propensity for IES. In addition, expression of the integrin β4 subunit was reduced in surgically resected specimens of CIS of the urinary bladder. Conclusion: The results indicate that a reduction in integrin β4 plays a role in IES of CIS of the urinary bladder through enhanced migration on laminin.

Access to Document (DOI)

Bilateral nonpalpable breast carcinomas in a patient with BRCA2 germ line mutation and past history of osteosarcoma.

Kuno T, Fukutomi T, Akashi-Tanaka S, Nanasawa T, Kanai Y, Tsuda H, Nomizu T, Miki Y.

Breast Cancer (Breast Cancer) 6 ( 1 ) 51 - 54 1999

Accepted, ISSN 13406868

A 34-year-old premenopausal woman developed asynchronous bilateral nonpalpable breast cancers at the age of 32 and 34 years. She had undergone amputation of her left lower leg because of osteosarcoma at the age of 16. Her mother had been diagnosed with breast cancer at the age of 45. The clinicopathological features of the two breast tumors in this patient closely resembled each other; both were nonpalpable, and detectable only by helical CT scan. Histologically, they consisted mainly of an intraductal component with small grade 3 invasive foci. In addition, both tumors estrogen receptor (ER) status was negative, and both were positive for c-erbB-2 protein on immunohistochemical staining. A missense germ line mutation of BRCA2 (exon 25 codon 3118; Met31 1 8Thr) was detected in this patient. These data may provide useful information on the carcinogenesis and biological behavior of breast cancers which develop in patients with BRCA2 germ line mutations.

Access to Document (DOI)

　 Previous page - Next page 　