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Papers - KANAI Yae

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Dominant negative inhibition of the association between β-catenin and c-erbB-2 by N-terminally deleted β-catenin suppresses the invasion and metastasis of cancer cells.

Shibata T, Ochiai A, Kanai Y, Akimoto S, Gotoh M, Yasui N, Machinami R, Hirohashi, S.

Oncogene (Oncogene) 13 ( 5 ) 883 - 889 1996

ISSN 09509232

Aberrant tyrosine phosphorylation of β-catenin inactivates the E-cadherin-mediated cell adhesion and invasion suppressor system in cancer cells. Elucidation of the association between β-catenin and c-erbB-2 protein prompted us to investigate whether interference with this interaction can change the invasive phenotype. In a human gastric cancer cell line, TMK-1, N-terminally deleted β-catenin, which binds to c-erbB-2 but not to cadherin, inhibited the association between endogenous β-catenin and c-erbB-2 protein, and suppressed the tyrosine phosphorylation of β-catenin. Cells expressing truncated β-catenin exhibited markedly reduced invasiveness in vitro and peritoneal metastasis in vivo, and developed an epithelial morphology. These results suggest that tyrosine phosphorylation of β-catenin regulated by c-erbB-2 protein may play an important role in the invasion, metastasis and morphogenesis of cancer cells and that inhibition of the aberrant tyrosine phosphorylation of β-catenin effectively prevents invasion and metastasis of cancer cells.

c-erbB-2 gene product directly associates with β-catenin and plakoglobin.

Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S, Hirohashi S.

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications) 208 ( 3 ) 1067 - 1072 1995

Accepted, ISSN 0006291X

Association of the c-erbB-2 oncogene product with the cadherin-catenin complex has been demonstrated in human cancer cell lines. Although β-catenin and plakoglobin have been proven to be crucial for the association, no previous study has shown whether the interactions are direct or indirect. In the present study, the c-erbB-2 gene product was shown by far-Western blotting analysis to associate directly with both β-catenin and plakoglobin through its cytoplasmic domain core region, which showed extensive homology with epidermal growth factor receptor. These data suggest that c-erbB-2-induced signaling is also directly liked to the cadherin-mediated cell adhesion and "invasion-suppressor" system through β-catenin and plakoglobin in cancers. © 1995 Academic Press. All rights reserved.

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Expression of N-cadherin and α-catenin in astrocytomas and glioblastomas.

Shinoura N, Paradies NE, Warnick RE, Chen H, Larson JJ, Tew JJ, Simon M, Lynch RA, Kanai Y, Hirohashi S, and et al.

Br J Cancer (British Journal of Cancer) 72 ( 3 ) 627 - 633 1995

Accepted, ISSN 00070920

We examined levels of mRNA and protein for N-cadherin, the predominant cadherin in neural tissues, and mRNA levels for the cadherin-associated protein, alpha-catenin, in a series of gliomas and in glioblastoma cell lines. mRNA levels for N-cadherin and alpha-catenin were significantly higher in glioblastomas than in low-grade astrocytomas or normal brain, while the levels of intact N-cadherin protein were similar in glioblastomas, low-grade astrocytomas and brain. In addition, there was no consistent relationship between invasiveness and expression of N-cadherin and alpha-catenin in highly invasive vs minimally invasive tumours within the same histopathological grade. To assess further the relationship between cadherin expression and neural tumour invasion, we measured N-cadherin expression, calcium-dependent cell adhesion and motility of several glioblastoma cell lines. While all N-cadherin-expressing lines were adhesive, no correlation was seen between the level of N-cadherin expression and cell motility. Together, these findings imply that, in contrast to the role played by E-cadherin in carcinomas, N-cadherin does not restrict the invasion of glioblastomas. © 1995 Stockton Press. All rights reserved.

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Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas.

Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S.

Proc Natl Acad Sci USA (Proceedings of the National Academy of Sciences of the United States of America) 92 ( 16 ) 7416 - 7419 1995

Accepted, ISSN 00278424

E-Cadherin, a cell adhesion molecule, which plays a key role in maintaining the epithelial phenotype, is regarded as an invasion-suppressor gene in light of accumulating evidence from in vitro experiments and clinical observations. In an attempt to clarify the mechanism responsible for inactivation of this gene in carcinomas, we investigated the methylation state around the promoter region by digestion of DNA with the methylation- sensitive restriction enzyme Hpa II, as CpG methylation of the promoter has been postulated to be a mechanism of transcriptional inactivation of some genes. We found that E-cadherin expression-negative carcinoma cell lines were accompanied by the hypermethylation state, whereas E-cadherin-positive cell lines were not. Furthermore, treatment of E-cadherin-negative carcinoma cells with the demethylating agent 5-azacytidine resulted in reexpression of the gene and reversion of scattered spindle-shaped cells to cells with epithelial morphology. These results suggest that hypermethylation around the promoter may be a mechanism of E-cadherin inactivation in human carcinomas and that treatment of E-cadherin-inactivated cells with a demethylating agent may cause gene expression reversion leading to epithelial morphogenesis with acquisition of the homophilic cell-cell adhesive property.

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Analysis of the neurofibromatosis 2 gene in human breast and hepatocellular carcinomas.

Kanai Y, Tsuda H, Oda T, Sakamoto M, Hirohashi S.

Jpn J Clin Oncol (Japanese journal of clinical oncology) 25 ( 1 ) 1 - 4 1995

Accepted, ISSN 03682811

The neurofibromatosis 2 gene (NF2) mapped to chromosome 22q is a recently isolated tumor suppressor gene that participates in the tumorigenesis of cells of embryonic neural crest origin. The structural similarities between the NF2 product, merlin-schwannomin, and the band 4.1 family raise the possibility that merlin may participate in a wide range of cell activities, in which the cytoskeleton latticework has important roles to play. In order to examine the significance of NF2 in general carcinogenesis, comprehensive analyses of 68 cases of breast carcinoma, which shows frequent loss of heterozygosity at chromosome 22, and 48 hepatocellular carcinomas of different histological grade were performed. No mutation was detected by the polymerase chain reaction-single-strand conformation polymorphism method for six exons of NF2 in any of the cases examined, suggesting that NF2 may be less important in the tumorigenesis of breast and liver cancers than in that of cancers originating from the neural crest.

Point Mutation of the E–Cadherin Gene in Invasive Lobular Carcinoma of the Breast

Kanai Y., Oda T., Tsuda H., Ochiai A., Hirohashi S.

Japanese Journal of Cancer Research (Japanese Journal of Cancer Research) 85 ( 10 ) 1035 - 1039 1994.10

ISSN 09105050

Reduced or heterogeneous expression of E–cadherin has been demonstrated immunohistochemically in poorly differentiated carcinoma, which frequently shows weak intercellular adhesiveness and marked invasiveness. In vitro, not only reduced expression but also structural abnormalities of E–cadherin have been observed in human carcinoma cell lines which grow in a loosely adhering manner. To clarify the participation of structural abnormalities of E–cadherin in cancer invasion in vivo, sequence abnormalities were examined in the cadherin domain (exons 5, 6, 7 and 8) including the region essential for E–cadherin specific binding, using the polymerase chain reaction–single–strand conformation polymorphism method and direct sequencing in invasive lobular carcinoma of the breast, in which cancer cells become detached from each other and invade the stroma in a particularly scattered pattern. In 2 (10%) of the 20 cases examined, an identical sequence abnormality was detected in E–cadherin exon 7, i.e. a point mutation of codon 315 (AAT to AGT) which resulted in a single ainino acid substitution (asparagine to serine). This mutation may abolish the E–cadherin–mediated cell–cell adhesion and be at least partly responsible for the weak intercellular adhesiveness and scattered histological pattern of the tumor. Copyright © 1994, Wiley Blackwell. All rights reserved

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Role of serotonin in the progression of pulmonary hypertension

Hosoda Y., Kanai Y.

[Rinshō ketsueki] The Japanese journal of clinical hematology ([Rinshō ketsueki] The Japanese journal of clinical hematology) 35 ( 4 ) 376 - 380 1994.04

ISSN 04851439

From 0.5 to 3 days after subcutaneous injection of monocrotaline (MCT) 60 mg/kg, prominent accumulation of platelets in the pulmonary capillaries accompanied with significant elevation of the plasma serotonin level was observed. To clarify the role of serotonin, the in vivo and in vitro effects of the selective 5-HT2 receptor antagonist, DV-7028, on MCT-induced pulmonary hypertension were studied. Oral administration of DV-7028 (10 mg/kg, twice daily) significantly suppressed the MCT-induced elevation of pulmonary arterial pressure, right ventricular hypertrophy and medial thickening of the muscular-type pulmonary arteries which occurred 23 days after MCT administration. The plasma level achieved by oral administration of 10 mg/kg DV-7028 was more than 10(-7) M. The hyperreactivity to serotonin in isolated pulmonary artery segments from MCT-treated rats was significantly reduced by DV-7028 (10(-7) M). The present study suggests that serotonin, released from platelets and accumulated in pulmonary capillaries, contributes to the initiation and/or progression of pulmonary hypertension in MCT-treated rats.

Point mutation of the E-cadherin gene in invasive lobular carcinoma of the breast.

Kanai Y, Oda T, Tsuda H, Ochiai A, Hirohashi, S.

Jpn J Cancer Res 85 1035 - 1039 1994

Accepted

Alterations of the cadherin-catenin cell adhesion system in cancers.

Kanai Y, Oda T, Shimoyama Y, Ochiai A, Oyama T, Yoshiura K, Akimoto S, Yamada T, Hirohashi, S.

Princess Takamatsu Symp (Princess Takamatsu symposia) 24 51 - 62 1994

The E-cadherin-mediated cell adhesion system acts as an "invasion suppressor" system, which is widely considered to be inactivated when the expression of E-cadherin is reduced and/or heterogeneous. To further investigate the molecular mechanisms responsible for dysfunction of this system in cancers, we examined human carcinoma cell lines lacking tight cell-cell adhesion. In KATO-III, established from stomach cancer, a point mutation of the E-cadherin gene resulted in a mRNA splicing error and markedly reduced E-cadherin expression. In another stomach cancer cell line, MKN 45, an 18-bp deletion of the E-cadherin gene caused a mRNA splicing error and a 4-amino-acid deletion, which was considered to alter the conformation around the key Ca(2+)-binding motif. In these two cell lines, the wild-type allele of the E-cadherin locus, which was assigned to chromosome 16q, was lost. Also in vivo, we found mutation of E-cadherin in breast cancers, where allele loss on chromosome 16 has frequently been reported. Thus, dysfunction of E-cadherin could be caused by a combination of the loss of one allele and a mutation in the remaining allele. Homologous deletion of part of the alpha-catenin gene, resulting in markedly reduced expression, was observed in a human lung cancer cell line, PC9. Recently, we also found mutations of beta-catenin in human carcinoma cell lines. These findings indicate the possible involvement of genetic abnormalities of various components in inactivation of the E-cadherin-mediated "invasion suppressor system" in cancers.

c-erbB-2 gene product associates with catenins in human cancer cells.

Ochiai A, Akimoto S, Kanai Y, Shibata T, Oyama T, Hirohashi S.

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications) 205 ( 1 ) 73 - 78 1994

Accepted, ISSN 0006291X

Phosphorylation of β-catenin, an intracytoplasmic cadherin-binding protein, causes disruption of the cadherin-mediated cell adhesion system in cancer cells. A 185-kDa phosphorylated protein, identified as the c-erbB-2 gene product, was co-immunoprecipitated with the E-cadherin-catenin complex. Association of the c-erbB-2 gene product with the cadherin-catenin complex was proved to be mediated through β-catenin and plakoglobin using an in vitro protein-protein precipitation system. These results indicate that the c-erbB-2 gene product associates with catenins and may regulate the cell adhesion and invasive growth of cancer. © 1994 Academic Press, Inc.

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A truncated β-catenin disrupts the interaction between E-cadherin and α-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines.

Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara K, Nagafuchi A, Tsukita S, Shibamoto S, Ito F, and et al.

Cancer Res (Cancer Research) 54: ( 23 ) 6282 - 6287 1994

Accepted, ISSN 00085472

Cadherin cell adhesion molecules play an essential role in creating tight intercellular association and are considered to work as an invasion suppressor system of cancer cells. They form a molecular complex with catenins, a group of cytoplasmic proteins including α- and β-catenins. While α-catenin has been demonstrated to be crucial for cadherin (unction, the role of β-catenin is not yet fully understood. In this study, we analyzed the cadherin-catenin system in two human cell lines, HSC-39 and its putative subline HSC-40A, derived from a signet ring cell carcinoma of stomach. These cells grow as loose aggregates or single cells, suggesting that their cadherin system is not functional. In these cell lines, an identical 321-base pair in-frame mRNA deletion of β-catenin was identified; this led to a 107-amino-acid deletion in the NH2-terminal region of the protein. Southern blot analysis disclosed a homozygous deletion in part of the β-catenin gene. On the other hand, these cells expressed E-cadherin, α-catenin, and plakoglobin of normal size. Immunoprecipitation analyses showed that E-cadherin was coprecipitated with the mutated β-catenin but not with α-catenin, and antibodies against β-catenin did not copurify α-catenin. However, the recombinant fusion protein containing wild-type β-catenin precipitated α-catenin from these cells. These results suggest that the dysfunction of E-cadherin in these cell lines is due primarily to its failure to interact with α-catenin, and that this defect results from the mutation in β-catenin. Thus, it is most likely that the association between E-cadherin and α-catenin is mediated by β-catenin, and that this process is blocked by NH2-terminal deletion in β-catenin. These findings indicate that genetic abnormality of β-catenin is one of the mechanisms responsible for loosening of cell-cell contact, and may be involved in enhancement of tumor invasion in human cancers. © 1994, American Association for Cancer Research. All rights reserved.

E-cadherin gene mutations in human gastric carcinoma cell lines.

Oda T, Kanai Y, Oyama T, Yoshiura K, Shimoyama Y, Birchmeier W, Sugimura T, Hirohashi S.

Proc Natl Acad Sci USA (Proceedings of the National Academy of Sciences of the United States of America) 91 ( 5 ) 1858 - 1862 1994

Accepted, ISSN 00278424

Reduced expression of E-cadherin has been regarded as one of the main molecular events involved in dysfunction of the cell-cell adhesion system, triggering cancer invasion and metastasis. However, even with a sufficient amount of E-cadherin, cell-cell adhesion is sometimes lost in 'diffusely invasive' human carcinomas. Ten human cancer cell lines, showing growth characterized morphologically by loose cell-cell adhesion, were analyzed for possible structural abnormalities of their expressed E-cadherin. Four of the cell lines showed strong mRNA and protein expression with no nucleotide sequence abnormalities, and mRNA was absent in four other cell lines. mRNA sequence was abnormal in the remaining two gastric carcinoma cell lines. In MKN45 (poorly differentiated adenocarcinoma), this involved a 12-bp in-frame deletion with strong expression of mRNA and protein. In KATO-III (signet ring cell carcinoma), there were four mRNA species with insertions of different sizes, among which the major transcripts (with a 7-bp insertion) caused a frameshift, and expression of both mRNA and protein was markedly reduced. In these two cell lines, DNA mutations were detected around exon-intron junctions, revealing that aberrant RNA splicing was the cause of the mRNA abnormalities. In addition, the wild-type allele of the E-cadherin locus was lost, suggesting that the E-cadherin gene had been inactivated by two hits (mutation and allele loss), similar to the mechanism for inactivation of tumor suppressor genes.

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Abnormalities of cell adhesion molecules in multistage carcinogenesis

Kanai Y., Shimoyama Y., Oda T., Hirohashi S.

Gann Monographs on Cancer Research (Gann Monographs on Cancer Research) 42 127 - 138 1994

ISSN 00720151

Invasion and metastasis are later but critically important steps in multistage carcinogenesis. The inactivation of E (epithelial)-cadherin, which is a Ca2+-dependent cell-cell adhesion molecule, may trigger the release of cancer cells from the cancer nests. In fact, the invasion suppressing function of E-cadherin has been shown in in vitro studies. Furthermore, E-cadherin expression was strong in well differentiated carcinomas, whereas generally reduced in undifferentiated ones showing the strong invasive property. In spite of the above general rule, we found that a sizable proportion of undifferentiated gastric adenocarcinomas showing scattered histological growth pattern had definite E-cadherin expression. Therefore, human carcinoma cell lines lacking tight cell-cell adhesion were examined to clarify if alterations in catenins, which are cytoplasmic proteins interacting with cadherins, and/or structural abnormalities of normally expressed E-cadherin caused the dysfunction of the cell-cell adhesion system. Homologous deletion of part of the α-catenin gene with markedly reduced expression was observed in a human lung cancer cell line, PC9. mRNA sequence abnormalities of E-cadherin were detected in two human gastric cancer cell lines, MKN 45 and KATO-III. The wild-type allele of E-cadherin locus was lost in the two cell lines, indicating that E-cadherin gene was inactivated by a combination of loss of gene and mutation, similar to the mechanism which inactivated tumor suppressor genes. These findings suggested that varying genetic abnormalities of cell adhesion molecules could participate in multistage carcinogenesis, especially in the processes of invasion and metastasis.

Role of 5-hydroxytryptamine in the progression of monocrotaline induced pulmonary hypertension in rats.

Kanai Y, Hori S, Tanaka T, Yasuoka M, Watanabe K, Aikawa N, Hosoda Y.

Cardiovasc Res (Cardiovascular Research) 27 ( 9 ) 1619 - 1623 1993

Accepted, ISSN 00086363

Objective: The aim was to clarify the role of serotonin (5-hydroxytryptamine, 5-HT) in monocrotaline induced pulmonary hypertension. Methods: Plasma 5-HT levels, pulmonary capillary platelet count, and vascular responsiveness to 5-HT were evaluated in the model. The effects of the selective 5-HT2 receptor antagonist, DV- 7028, on the development of pulmonary hypertension were also investigated. Results: Plasma 5-HT was raised 12 h to 3 d after monocrotaline administration (60 mg·kg-1), coinciding with accumulation of platelets in the pulmonary circulation. Isolated pulmonary arteries showed hyperreactivity to 5-HT at 14 and 21 d after monocrotaline. Administration of DV-7028 (20 mg·kg-1·d-1) attenuated the increase in pulmonary arterial pressure, right ventricular hypertrophy, and medial thickening of the pulmonary arteries. Conclusions: The present study suggests that 5-HT released from platelets contributes to the initiation and progression of monocrotaline induced pulmonary hypertension.Cardiovascular Research 1993;27:1619-1623.

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Cloning of the human α-catenin cDNA and its aberrant mRNA in a human cancer cell line.

Oda T, Kanai Y, Shimoyama Y, Nagafuchi A, Tsukita S, Hirohashi S.

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications) 193 ( 3 ) 897 - 904 1993

Accepted, ISSN 0006291X

Cadherin and catenin compose cell adhesion complex and are indispensable for tight cell-cell adhesion. Dysfunction of this adhesion complex causes dissociation of cancer cells from primary tumor nodules, thus possibly contributing to cancer invasion and metastasis. In this report, we present the human α-caienin sequence. Human α-catenin showed extensive homology with that of mouse, i.e., 91.8% and 99.3% at the nucleic acid and amino acid levels, respectively, indicating that this molecule has been evolutionarily conserved in mammals. Characterization of the mRNA sequence of α-catenin in PC9 was also carried out, and two distinct abnormal sequences, i.e., one of 957 bp deletion resulting in a 319-amino-acid deletion and another of 761 bp deletion resulting in a frameshift, were identified. These deletions were probably produced by an error of RNA splicing, presenting one possible mechanism for the loss of intact α-catenin expression. © 1993 Academic Press, Inc.

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Pulmonary venoocclusive disease in a patient with systemic lupus erythematosus.

Kishida Y, Kanai Y, Kuramochi S, Hosoda Y.

J Rheumatol (Journal of Rheumatology) 20 ( 12 ) 2161 - 2162 1993

Accepted, ISSN 0315162X

Giant Cell Fibroblastoma: A Case Report and lmmunohistochemical Comparison with Ten Cases of Dermatofibrosarcoma Protuberans

Kanai Y., Mukai M., Sugiura H., Tanaka Y., Mukai K., Ukiyama E., Yokoyama J., Iri H., Hosoda Y.

Pathology International (Pathology International) 41 ( 7 ) 552 - 560 1991.07

ISSN 13205463

A 7 year old boy with giant cell fibroblastoma (GCF) of the skin and subcutaneous tissue of the right chest wall is described. To date, the histogenesis of GCF has not been clarified. The reason for the diversity of immunohistochemical data among various authors may be because the specimens studied were from only part of the lesion, or reduction of antigenicity through the preparation process. However, our findings based on studies of many specimens from various parts of the tumor for accurate immunohistochemical evaluation suggest that GCF may be a myofibro histiocytic tumor. Recently, the suggestion that GCF is a juvenile form of dermatofibrosarcoma protuberans (DFSP) has been reported. In addition to the present case, we performed immunohistochemical examination of 10cases of definitely diagnosed DFSP for comparison. The immunohistochemical characteristics of these two neoplasms were concordant. However, from clinical and morphological viewpoints, it seems premature to recognize GCF as a juvenile form of DFSP. Acta Pathol Jpn 41: 552–560, 1991. Copyright © 1991, Wiley Blackwell. All rights reserved

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Giant cell fibroblastoma. A case report and immunohistochemical comparison with ten cases of dermatofibrosarcoma protuberans.

Kanai Y, Mukai M, Sugiura H, Tanaka Y, Mukai K, Ukiyama E, Yokoyama J, Iri H, Hosoda Y.

Acta Pathol Jpn 41 552 - 560 1991

77-year-old woman with proteinuria: saddle nose and disorders in the central nervous system.

Saruta T, Sato M, Suzuki H, Akizuki M, Ushioda T, Hosoda Y, Yamawaki T, Kuramochi S, Sakaguchi H, Kanai Y.

Keio J Med 39 193 - 205 1990

Accepted

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