Papers - SUZUKI Hiromu

Genetic Dissection of Differential Signaling Threshold Requirements for the Wnt/beta-Catenin Pathway In Vivo

Michael Buchert, Dimitris Athineos, Helen E. Abud, Zoe D. Burke, Maree C. Faux, Michael S. Samuel, Andrew G. Jarnicki, Catherine E. Winbanks, Ian P. Newton, Valerie S. Meniel, Hiromu Suzuki, Steven A. Stacker, Inke S. Nathke, David Tosh, Joerg Huelsken, Alan R. Clarke, Joan K. Heath, Owen J. Sansom, Matthias Ernst

PLOS GENETICS ( PUBLIC LIBRARY SCIENCE )  6 ( 1 ) e1000816  2010.01  [Refereed]

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Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/beta-catenin pathway, we challenged the allele combinations by genetically restricting intracellular beta-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/beta-catenin signaling in the form of an allelic series of mouse mutants. Different permissive Wnt signaling thresholds appear to be required for the embryonic development of head structures, adult intestinal polyposis, hepatocellular carcinomas, liver zonation, and the development of natural killer cells. Furthermore, we identify a homozygous Apc allele combination with Wnt/beta-catenin signaling capacity similar to that in the germline of the Apc(min) mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apc(min) mice arise independently of intestinal tumorigenesis. Together, the present genotype phenotype analysis suggests tissue-specific response levels for the Wnt/beta-catenin pathway that regulate both physiological and pathophysiological conditions.

DOI PubMed

Molecular analysis of single isolated glands in gastric cancers and their surrounding gastric intestinal metaplastic mucosa

Tamotsu Sugai, Wataru Habano, Yu-Fei Jiao, Minoru Toyota, Hiromu Suzuki, Mitsunori Tsukahara, Hitohiko Koizuka, Risaburo Akasaka, Keisuke Koeda, Go Wakabayashi, Kazuyuki Suzuki

ONCOLOGY REPORTS ( SPANDIDOS PUBL LTD )  23 ( 1 ) 25 - 33  2010.01  [Refereed]

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The biological properties and underlying genetics of gastric cancer and gastric intestinal metaplasia evolve with neoplastic progression from the genetics of the original gland cell. PCR assay with crypt isolation was used in tumors from 20 patients to examine microsatellite alterations (allelic imbalance at 17p, 5q, 18q, 3p, 4p, and 9p, and microsatellite instability) in glands from each tumor and from intestinal metaplastic lesions. Tumor specimens were processed as either pooled-gland samples or single-gland samples. Pooled gland sample was composed of 10-20 tumor glands, intestinal metaplastic glands, or nonmetaplastic glands. Single gland sample was 10 tumor glands from tumor and single gland sample was 5 gastric intestinal metaplastic and 5 nonmetaplastic glands from its surrounding metaplastic mucosa. Multiple genetic alterations were found in individual tumor glands, with various subclonal expansions seen within the same tumor. Although microsatellite instability was found in 2 of 20 tumor single-gland samples, none was detected in metaplastic single-gland samples. Most cancers appear to have a heterogeneous composition. On the other hand, microsatellite alterations were also detected within the non-metaplastic as well as intestinal metaplastic single-gland samples. In conclusion, the present data on tumor and corresponding intestinal metaplastic and nonmetaplastic glands suggest that genetic alterations already occur within the surrounding of the noncancerous mucosa.

DOI PubMed

Epigenetic Drivers of Genetic Alterations

Minoru Toyota, Hiromu Suzuki

EPIGENETICS AND CANCER, PT A ( ELSEVIER ACADEMIC PRESS INC )  70   309 - 323  2010  [Refereed]

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DNA methylation plays a key role in the silencing of cancer-related genes, thereby affecting numerous cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion, and angiogenesis. DNA methylation also affects the expression of genes involved in maintaining the integrity of the genome through DNA repair and detoxification of reactive oxygen species. Here, we discuss how epigenetic changes lead to genetic alterations, including microsatellite instability and nucleotide and chromosomal alterations. Epigenetic inactivation of hMLH1 is a major cause of microsatellite instability in sporadic colorectal cancers, and germline epimutation of hMLH1 and hMSH2 is a cause of hereditary nonpolyposis colorectal cancers, which do not show mutation of mismatch repair genes. Epigenetic inactivation of MGMT is often associated with G:C-to-A:T mutations in K-ras and p53, while epigenetic inactivation of BRCA1, WRN, FANCF, and CHFR impairs the machinery involved in maintaining genomic integrity. Epigenetic alteration of the genes involved in the induction of senescence is often associated with cancers showing mutations in the Ras signaling pathway. In addition to regional hypermethylation, global hypomethylation is also a common feature of tumors. Hypomethylation of short and long interspersed repetitive elements has been reported, and hypomethylation affecting the integrity of the genome has been observed in ICF syndrome and various cancers. Dissection of the epigenetic drivers of genetic instability may be important for the development of novel approaches to the treatment of cancer. (C) 2010, Elsevier Inc.

DOI PubMed

Molecular mechanisms involved in epigenetic alterations in cancer

Minoru Toyota, Hiromu Suzuki, Takahiro Nishizaka, Akiko Sato, Toshiharu Yamashita

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. )  37 ( 9 ) 1650 - 1653  2010  [Refereed]

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Epigenetic alterations such as DNA methylation and histone modification play a role in gene silencing in tumorigenesis. DNA methylation affects the expression of genes involved in cell cycle checkpoint, apoptosis, and DNA repair. Recently, epigenetic alterations are shown to play a role in silencing microRNA. Mutations of DNA methyltransferase and histone modification enzymes such as DNMT3A, UTX and EZH2 have been shown in various types of tumors. Genes involved in epigenetic regulation may be novel targets of cancer therapy in the near future.

PubMed

Integrated analysis of genetic and epigenetic alterations in cancer

Minoru Toyota, Hiromu Suzuki, Eichiro Yamamoto, Hiroo Yamano, Kohzoh Imai, Yasuhisa Shinomura

EPIGENOMICS ( FUTURE MEDICINE LTD )  1 ( 2 ) 291 - 299  2009.12  [Refereed]

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A proposed genetic model describing the transition from normal colonic epithelium to malignant cancer involves mutation of a number of key oncogenes and tumor suppressor genes. However, only subsets of colorectal cancers contain such mutations. Moreover, the heterogeneous pattern of tumor mutations suggests there are multiple alternative pathways leading to colonic tumorigenesis. These alternative pathways involve epigenetic alterations such as the methylation of multiple CpG islands, termed the CpG island methylator phenotype, and cancers with CpG island methylator phenotype show distinct genetic and clinicopathological features. The causes of these epigenetic alterations are still not fully understood, but exogenous pathogens such as Helicobacter pylori and Epstein Barr virus, and the chromosomal translocations seen in leukemia, have all been shown to induce epigenetic alterations of genes.

DOI PubMed

Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

Yasuhiro Goto, Keiko Shinjo, Yutaka Kondo, Lanlan Shen, Minoru Toyota, Hiromu Suzuki, Wentao Gao, Byonggu An, Makiko Fujii, Hideki Murakami, Hirotaka Osada, Tetsuo Taniguchi, Noriyasu Usami, Masashi Kondo, Yoshinori Hasegawa, Kaoru Shimokata, Keitaro Matsuo, Toyoaki Hida, Nobukazu Fujimoto, Takumi Kishimoto, Jean-Pierre J. Issa, Yoshitaka Sekido

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH )  69 ( 23 ) 9073 - 9082  2009.12  [Refereed]

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Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):9073-82]

DOI PubMed

Elevated Dnmt3a Activity Promotes Polyposis in Apc(Min) Mice by Relaxing Extracellular Restraints on Wnt Signaling

Michael S. Samuel, Hiromu Suzuki, Michael Buchert, Tracy L. Putoczki, Niall C. Tebbutt, Therese Lundgren-May, Aliki Christou, Melissa Inglese, Minoru Toyota, Joan K. Heath, Robyn L. Ward, Paul M. Waring, Matthias Ernst

GASTROENTEROLOGY ( W B SAUNDERS CO-ELSEVIER INC )  137 ( 3 ) 902 - 913  2009.09  [Refereed]

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BACKGROUND & AIMS: Aberrant DNA methylation is a common early event in neoplasia, but it is unclear how this relates to dysregulation of DNA (cytosine-5) methyltransferases (Dnmts). Here we use knock-in transgenic mice to investigate the consequences of intestinal epithelium-specific overexpression of de novo Dnmt3a. METHODS: A novel gene targeting strategy, based on the intestinal epithelium-specific, uniform expression of the A33 glycoprotein, is employed to restrict Dnmt3a overexpression in homozygous A33(Dnmt3a) mutant mice. RESULTS: A33(Dnmt3a) mice infrequently develop spontaneous intestinal polyps. However, when genetically challenged, tumor multiplicity in A33(Dnmt3a);Apc(Min) compound mice is 3-fold higher than in Apc(Min) mice. Although we observe a requirement for spontaneous loss of heterozygosity of the adenomatous polyposis coli (Apc) gene to trigger tumorigenesis in Apc(Min) mice, lesions in A33(Dnmt3a); Apc(Min) mice frequently retain the wild-type Apc allele. However, epithelia from normal mucosa and polyps of A33(Dnmt3a);Apc(Min) mice show hypermethylation-mediated transcriptional silencing of the Writ antagonists Sfrp5, and to a lesser extent, Sfrp1 and increased nuclear beta-catenin alongside activation of the Wnt-target gene Axin2/Conductin. Conversely, enforced Sfrp5 expression suppresses canonical Writ-signaling more effectively in wildtype than in Apc(Min) cells. CONCLUSIONS: Aberrant activation of the canonical Wnt pathway, either by mono-allelic Apc loss or transcriptional silencing of Sfrp5 is largely insufficient to promote polyposis, but epistatic interactions between these genetic and epigenetic events enables initiation and promotion of disease. This mechanism is likely to play a role in human colorectal cancer, because we also show that elevated DNMT3A expression coincides with repressed SFRP5 and enhanced AXIN2/CONDUCTIN expression in paired patient biopsies.

DOI PubMed

DNAメチル化の網羅的解析によって解明された、多発性骨髄腫におけるRASD1遺伝子不活化とデキサメサゾン耐性の相関(Genomic Screening by DNA Methylation Revealed an Association between RASD 1 Inactivation and Dex Resistance in MM)

野島 正寛, 丸山 玲緒, 安井 寛, 鈴木 拓, 佐々木 泰史, 麻奥 英毅, 酒井 基, 石田 禎夫, 森 満, 今井 浩三, 時野 隆至, 豊田 実, 篠村 恭久

日本癌学会総会記事 ( (一社)日本癌学会 )  68回   224 - 224  2009.08

p53誘導性膜貫通蛋白質hCLCA2は癌細胞移動/接着を制御する(hCLCA2, a p53 inducible transmembrane protein regulates cancer cell migration and adhesion)

佐々木 泰史, 安保 直樹, 鹿島 理沙, 井戸川 雅史, 鈴木 拓, 豊田 実, 今井 浩三, 篠村 恭久, 時野 隆至

日本癌学会総会記事 ( (一社)日本癌学会 )  68回   140 - 140  2009.08

潜在的腫瘍抑制因子CHFRはNFκB抑制を介してインターロイキン-8を下方制御する(CHFR, a potential tumor suppressor, downregulates interleukin-8 via inhibition of NF-kappaB)

鹿島 理沙, 豊田 実, 見田 裕章, 鈴木 拓, 井戸川 雅史, 荻 和弘, 佐々木 泰史, 時野 隆至

日本癌学会総会記事 ( (一社)日本癌学会 )  68回   155 - 155  2009.08

p53応答配列のゲノム網羅的in silico解析によるp53誘導性non-coding RNAの同定(Genome wide in silico analysis of p53 response elements identified non-coding RNA regulated by p53)

高丸 博之, 丸山 玲緒, 豊田 実, 鈴木 拓, 佐々木 泰史, 野島 正寛, 明石 浩史, 今井 浩三, 篠村 恭久, 時野 隆至

日本癌学会総会記事 ( (一社)日本癌学会 )  68回   141 - 141  2009.08

CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-κB

L. Kashima, M. Toyota, M. Toyota, H. Mita, H. Suzuki, H. Suzuki, M. Idogawa, K. Ogi, Y. Sasaki, T. Tokino

Oncogene   28   2643 - 2653  2009.07

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The mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger domains) is silenced in various human cancers by promoter hypermethylation, suggesting that CHFR is a tumor suppressor. Here, we show that CHFR functions as a negative regulator of the nuclear factor-κB (NF-κB) pathway. Expression of CHFR inhibited NF-κB reporter activity, whereas knockdown of CHFR activated reporter activity. These activities are independent of its RING finger domain. Furthermore, we found that CHFR physically interacts with p65 in cells. Electrophoretic mobility shift assays (EMSAs) and ELISA-based NF-κB-binding assays showed that CHFR negatively regulated transcriptional activity of p65. In addition, our data show that interleukin (IL)-8 is significantly downregulated by CHFR, and that the migration of human endothelial cells is suppressed in culture medium conditioned from CHFR-expressing cancer cells. Using a xenograft model, we show that neovascularization is suppressed by adenovirus-mediated transfer of CHFR. These results indicate that expression of CHFR markedly reduces the expression of IL-8 through the inhibition of NF-κB. As the NF-κB signaling pathway plays a critical role in the development and progression of cancer, our findings show the functional relationship between epigenetic alteration and inflammation/angiogenesis in human cancer cells, thereby showing several potential targets for therapeutic intervention. © 2009 Macmillan Publishers Limited All rights reserved.

DOI PubMed

Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma

Masanori Nojima, Reo Maruyama, Hiroshi Yasui, Hiromu Suzuki, Yumiko Maruyama, Isao Tarasawa, Yasushi Sasaki, Hideki Asaoku, Hajime Sakai, Toshiaki Hayashi, Mitsuru Mori, Kohzoh Imai, Takashi Tokino, Tadao Ishida, Minoru Toyota, Yasuhisa Shinomura

CLINICAL CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH )  15 ( 13 ) 4356 - 4364  2009.07  [Refereed]

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Purpose: Epigenetic changes such as DNA methylation play a key role in the development and progression of multiple myeloma. Our aim in the present study was to use genomic screening to identify genes targeted for epigenetic inactivation in multiple myeloma and assess their role in the development of resistance to dexamethasone. Experimental Design: Gene expression was examined using microarray screening, reverse transcription-PCR, and real-time quantitative PCR. DNA methylation was examined using bisulfite PCR, bisulfite sequencing, and bisulfite pyrosequencing in 14 multiple myeloma cell lines, 87 multiple myeloma specimens, and 12 control bone marrow samples. WST-8 assays were used to assess cell viability after treatment with 5-aza-2'-deoxycytidine and/or dexamethasone. Results: Microarray analysis was done to screen for genes up-regulated by 5-aza-2'-deoxycytidine. In RPMI8226 cells, 128 genes were up-regulated, whereas 83 genes were up-regulated in KMS12PE cells. Methylation of 22 genes with CpG islands in their 5' regions, including RASD1, was confirmed. Methylation of RASD1 was associated with its inactivation, which correlated with resistance to dexamethasone. Treating multiple myeloma cells with 5-aza-2'-deoxycytidine restored sensitivity to dexamethasone. Methylation of RASD1 was also detected in a subset of primary multiple myeloma specimens, and the levels of methylation were increased after repeated antitumor treatments. Gene signature analysis revealed various genes to be synergistically induced by treatment with a combination of 5-aza-2'-deoxycytidine plus dexamethasone. Conclusion: Our findings indicate that epigenetic inactivation of genes, including RASD1, plays a key role in the development of dexamethasone resistance in multiple myeloma. Moreover, they show the utility of demethylation therapy in cases of advanced multiple myeloma.

DOI PubMed

A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth

Hiroaki Mita, Minoru Toyota, Fumio Aoki, Hirofumi Akashi, Reo Maruyama, Yasushi Sasaki, Hiromu Suzuki, Masashi Idogawa, Lisa Kashima, Kazuyoshi Yanagihara, Masahiro Fujita, Masao Hosokawa, Masanobu Kusano, Sorin Vasile Sabau, Haruyuki Tatsumi, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

BMC CANCER ( BIOMED CENTRAL LTD )  9   198  2009.06  [Refereed]

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Background: Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS), which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. Methods: DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. Results: DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20) of gastric cancer cell lines (8-18-fold amplification) and 4.7% (4/86) of primary gastric tumors (8-50-fold amplification). KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild-type KRAS resulted in the inhibition of cell growth and suppression of p44/42 MAP kinase and AKT activity. Conclusion: Our study highlights the utility of DGS for identification of copy-number alterations. Using DGS, we identified KRAS as a gene that is amplified in human gastric cancer. We demonstrated that gene amplification likely forms the molecular basis of overactivation of KRAS in gastric cancer. Additional studies using a larger cohort of gastric cancer specimens are required to determine the diagnostic and therapeutic implications of KRAS amplification and overexpression.

DOI PubMed

A Single Recombinant Adenovirus Expressing p53 and p21-targeting Artificial microRNAs Efficiently Induces Apoptosis in Human Cancer Cells

Masashi Idogawa, Yasushi Sasaki, Hiromu Suzuki, Hiroaki Mita, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

CLINICAL CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH )  15 ( 11 ) 3725 - 3732  2009.06  [Refereed]

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Purpose: Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. The activation of p53 induces either cell cycle arrest or apoptosis. Cell cycle arrest in response to p53 activation is mediated primarily through the induction of the cyclin-dependent kinase inhibitor p21. Because p21 also has an inhibitory effect on p53-mediated apoptosis, the suppression of p53-induced p21 expression would be expected to result in the preferential induction of apoptosis. However, p21 also has tumor-suppressive properties. In this study, we developed an adenovirus vector that expresses p53 and suppresses p21 simultaneously to enhance p53-mediated apoptosis. Experimental Design: We constructed a replication-deficient recombinant adenovirus (Ad-p53/miR-p21) that enabled cocistronic expression of the p53 protein and artificial microRNAs that targeted p21, and examined the therapeutic effectiveness of this vector in vitro and in vivo. Results: The levels of p21 were significantly attenuated following infection with Ad-p53/miR-p21. In colorectal and hepatocellular carcinoma cells, infection with Ad-p53/miR-p21 augmented apoptosis as compared with an adenovirus that expressed p53 alone (Ad-p53/miR-control). Ad-p53/miR-p21 also significantly increased the chemosensitivity of cancer cells to adriamycin (doxorubicin). In a xenograft tumor model in nude mice, tumor volume was significantly decreased following the direct injection of Ad-p53/miR-p21 into the tumor, as compared with the injection of Ad-p53/miR-control. Conclusion: These results suggest that adenovirus-mediated transduction of p53 and p21-specific microRNAs may be useful for gene therapy of human cancers.

DOI PubMed

Cancer epigenomics: implications of DNA methylation in personalized cancer therapy.

Minoru Toyota, Hiromu Suzuki, Toshiharu Yamashita, Koichi Hirata, Kohzoh Imai, Takashi Tokino, Yasuhisa Shinomura

Cancer science   100 ( 5 ) 787 - 91  2009.05  [Refereed]  [International journal]

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Genetic alterations in cancer can provide information for predicting a tumor's sensitivity to chemotherapeutic drugs. But although such information is certainly useful, the relatively low frequency of mutations seen in many cancers limits the utility of pharmacogenomics in large numbers of cancer patients, necessitating consideration of other approaches. Epigenetic changes such as DNA methylation are a hallmark of human cancers. Methylation of genes involved in DNA repair and maintaining genome integrity (e.g. MGMT, hMLH1, WRN, and FANCF), and cell-cycle checkpoint genes (e.g. CHFR and 14-3-3 sigma, CDK10, and p73), all reportedly influence the sensitivity to chemotherapeutic drugs, suggesting that DNA methylation could serve as a molecular marker for predicting the responsiveness of tumors to chemotherapy. However, the comprehensive study of pharmacoepigenomics awaits the advent of genome-wide analysis of DNA methylation using microarrays and next-generation sequencers.

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p53により発現抑制される分泌性増殖因子HDGFの同定 胃癌組織における発現解析

佐々木 泰史, 井戸川 雅史, 鈴木 拓, 豊田 実, 今井 浩三, 篠村 恭久

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  106 ( 臨増総会 ) A234 - A234  2009.03

DNAメチル化により引き起こされるSda糖鎖発現抑制の炎症発癌における意義

河村 由紀, 豊田 実, 河村 裕, 小西 文雄, 斉藤 幸夫, 鈴木 拓, 今井 浩三, 土肥 多惠子

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  106 ( 臨増総会 ) A309 - A309  2009.03

Inflammation-related aberrant patterns of DNA methylation: detection and role in epigenetic deregulation of cancer cell transcriptome.

Suzuki H, Toyota M, Kondo Y, Shinomura Y

Methods in molecular biology (Clifton, N.J.)   512   55 - 69  2009  [Refereed]

DOI PubMed

Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma.

Goto Yasuhiro, Shinjo Keiko, Kondo Yutaka, Shen Lanlan, Toyota Minoru, Suzuki Hiromu, Gao Wentao, An Byonggu, Fujii Makiko, Murakami Hideki, Osada Hirotaka, Taniguchi Tetsuo, Usami Noriyasu, Kondo Masashi, Hasegawa Yoshinori, Shimokata Kaoru, Matsuo Keitaro, Hida Toyoaki, Fujimoto Nobukazu, Kishimoto Takumi, Issa Jean-Pierre J, Sekido Yoshitaka

Cancer research   69 ( 23 )  2009

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:Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B,

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