Details of a Researcher - SUZUKI Hiromu

Papers - SUZUKI Hiromu

Division display 181 - 200 of about 344 ／ All the affair displays >>

Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway

Katsuhiko Nosho, Hisayoshi Igarashi, Masanori Nojima, Miki Ito, Reo Maruyama, Shinji Yoshii, Takafumi Naito, Yasutaka Sukawa, Masashi Mikami, Wakana Sumioka, Eiichiro Yamamoto, Sei Kurokawa, Yasushi Adachi, Hiroaki Takahashi, Hiroyuki Okuda, Takaya Kusumi, Masao Hosokawa, Masahiro Fujita, Tadashi Hasegawa, Kenji Okita, Koichi Hirata, Hiromu Suzuki, Hiroyuki Yamamoto, Yasuhisa Shinomura

CARCINOGENESIS ( OXFORD UNIV PRESS ) 35 ( 4 ) 776 - 783 2014.04 [Refereed]

High miR-31 expression was associated with BRAF mutation and unfavourable survival in CRCs. Moreover, miR-31 inhibitor exhibited antitumour effect in colon cancer cell line, suggesting that miR-31 may be a useful biomarker and therapeutic target in CRC.BRAF is an important gene in colorectal cancers (CRCs) that is associated with molecular characterization and resistance to targeted therapy. Although microRNAs (miRNAs) are useful biomarkers of various cancers, the association between miRNA and BRAF in CRCs is undefined. Therefore, this study was conducted to identify a relationship between specific miRNA molecules and BRAF mutation in CRCs and serrated lesions. miRNA array was used for the measurement of 760 miRNAs in 29 CRCs. To assess the identified miRNAs, quantitative reverse transcriptionPCR was performed on 721 CRCs, 381 serrated lesions and 251 non-serrated adenomas. Moreover, proliferation and invasion assays were conducted using cell lines. miRNA array analysis revealed that microRNA-31 (miR-31)-5p was the most up-regulated miRNA in CRCs with mutated BRAF (V600E) compared with CRCs possessing wild-type BRAF (including cases with KRAS mutation). High miR-31 expression was associated with BRAF and KRAS mutations and proximal location (P < 0.0001). High miR-31 expression was related to cancer-specific mortality [multivariate hazard ratio 2.06, 95% confidence interval: 1.363.09, P 0.0008]. Functional analysis demonstrated that miR-31 inhibitor decreased cell invasion and proliferation. With regard to serrated lesions, high miR-31 expression was less frequently detected in hyperplastic polyps compared with other serrated lesions. In conclusion, associations were identified between miR-31, BRAF and prognosis in CRC. Transfection of miR-31 inhibitor had an antitumour effect. Thus, miR-31 may be a promising diagnostic biomarker and therapeutic target in colon cancers. Moreover, high miR-31 expression in serrated lesions suggested that miR-31 may be a key molecule in serrated pathway.

An updated review of gastric cancer in the next-generation sequencing era: Insights from bench to bedside and vice versa

Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata, Ryo Morita, Yoshihito Yoshida, Ritsuko Oikawa, Shinya Ishigooka, Shun-ichiro Ozawa, Yasumasa Matsuo, Kosuke Hosoya, Masaki Yamashita, Hiroaki Taniguchi, Katsuhiko Nosho, Hiromu Suzuki, Hiroshi Yasuda, Yasuhisa Shinomura, Fumio Itoh

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBLISHING GROUP INC ) 20 ( 14 ) 3927 - 3937 2014.04 [Refereed]

Gastric cancer (GC) is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs. Recent studies using next-generation sequencing (NGS) have revealed a number of potential cancer-driving genes in GC. Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4, a member of the cadherin gene family. Mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) have been found in 47% of GCs. Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC. Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery, such as DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs and microRNAs. Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings. The antihuman epidermal growth receptor 2 (HER2) antibody trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor (VEGFR)-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy. Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets, as well as useful biomarkers. In this review, we will summarize the recent advances in the understanding of the molecular pathogenesis of GC, focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Fusobacterium in Colonic Flora and Molecular Features of Colorectal Carcinoma

Tomomitsu Tahara, Eiichiro Yamamoto, Hiromu Suzuki, Reo Maruyama, Woonbok Chung, Judith Garriga, Jaroslav Jelinek, Hiro-o Yamano, Tamotsu Sugai, Byonggu An, Imad Shureiqi, Minoru Toyota, Yutaka Kondo, Marcos R. H. Estecio, Jean-Pierre J. Issa

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 74 ( 5 ) 1311 - 1318 2014.03 [Refereed]

Fusobacterium species are part of the gut microbiome in humans. Recent studies have identified overrepresentation of Fusobacterium in colorectal cancer tissues, but it is not yet clear whether this is pathogenic or simply an epiphenomenon. In this study, we evaluated the relationship between Fusobacterium status and molecular features in colorectal cancers through quantitative real-time PCR in 149 colorectal cancer tissues, 89 adjacent normal appearing mucosae and 72 colonic mucosae from cancer-free individuals. Results were correlated with CpG island methylator phenotype (CIMP) status, microsatellite instability (MSI), and mutations in BRAF, KRAS, TP53, CHD7, and CHD8. Whole-exome capture sequencing data were also available in 11 cases. Fusobacterium was detectable in 111 of 149 (74%) colorectal cancer tissues and heavily enriched in 9% (14/149) of the cases. As expected, Fusobacterium was also detected in normal appearing mucosae from both cancer and cancer-free individuals, but the amount of bacteria was much lower compared with colorectal cancer tissues (a mean of 250fold lower for Pan-fusobacterium). We found the Fusobacterium-high colorectal cancer group (FB-high) to be associated with CIMP positivity (P = 0.001), TP53 wild-type (P = 0.015), hMLH1 methylation positivity (P = 0.0028), MSI (P = 0.018), and CHD7/8 mutation positivity (P = 0.002). Among the 11 cases where whole-exome sequencing data were available, two that were FB-high cases also had the highest number of somatic mutations (a mean of 736 per case in FB-high vs. 225 per case in all others). Taken together, our findings show that Fusobacterium enrichment is associated with specific molecular subsets of colorectal cancers, offering support for a pathogenic role in colorectal cancer for this gut microbiome component. (C) 2014 AACR.

Colorectal Carcinomas With CpG Island Methylator Phenotype 1 Frequently Contain Mutations in Chromatin Regulators

Tomomitsu Tahara, Eiichiro Yamamoto, Priyanka Madireddi, Hiromu Suzuki, Reo Maruyama, Woonbok Chung, Judith Garriga, Jaroslav Jelinek, Hiro-o Yamano, Tamotsu Sugai, Yutaka Kondo, Minoru Toyota, Jean-Pierre J. Issa, Marcos R. H. Estecio

GASTROENTEROLOGY ( W B SAUNDERS CO-ELSEVIER INC ) 146 ( 2 ) 530 - + 2014.02 [Refereed]

BACKGROUND & AIMS: Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. METHODS: We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. RESULTS: We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate-dependent chromatin remodeling family. Somatic mutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P<.01) or CIMP-negative tumors (2 of 34 [6%]; P<.001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. CONCLUSIONS: Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.

The effect of IGF-I receptor blockade for human esophageal squamous cell carcinoma and adenocarcinoma

Yasushi Adachi, Hirokazu Ohashi, Arisa Imsumran, Hiroyuki Yamamoto, Yasutaka Matsunaga, Hiroaki Taniguchi, Katsuhiko Nosho, Hiromu Suzuki, Yasushi Sasaki, Yoshiaki Arimura, David P. Carbone, Kohzoh Imai, Yasuhisa Shinomura

TUMOR BIOLOGY ( SPRINGER ) 35 ( 2 ) 973 - 985 2014.02 [Refereed]

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and tumor development, and this pathway has not been well studied in human esophageal carcinomas. Esophageal cancer is one of the human cancers with the worst prognosis and has two main histologies: squamous cell carcinomas (ESCC) and adenocarcinoma (EAC). Previously, we have reported that detection of the IGF axis may be useful for the prediction of recurrence and poor prognosis of ESCC. We have also shown the successful therapy for several gastrointestinal cancers using recombinant adenoviruses expressing dominant negative IGF-IR (ad-IGF-IR/dn). The aim of this study is to develop potential targeted therapeutics to IGF-IR and to assess the effect of IGF-IR blockade in both of these types of esophageal cancer. We determined immunohistochemical expression of IGF-IR in a tissue microarray. We then assessed the effect of IGF-IR blockade on signal transduction, proliferation, apoptosis, and motility. Ad-IGF-IR/dn, a tyrosine kinase inhibitor, BMS-536924, and adenovirus expressing shRNA for IGF-IR were used. IGF-IR expression was common in both tumor types but not in normal tissues. IGF-IR was detected in metastatic sites at similar levels compared to the primary site. IGF-IR inhibition suppressed proliferation and colony formation in both cancers. IGF-IR blockades up-regulated both stress- and chemotherapy-induced apoptosis and reduced migration. Although IGF-IR/dn blocked ligand-induced activation of Akt-1 mainly, BMS-536924 effectively blocked both activation of Akt and MAPK. The IGF axis might play a key role in tumor progression of esophageal carcinomas. The IGF-IR targeting strategies might thus be useful anticancer therapeutics for human esophageal malignancies.

Epigenetic regulation of microRNA genes in colorectal cancer

Hiromu Suzuki, Eiichiro Yamamoto, Reo Maruyama

MicroRNA in Development and in the Progression of Cancer ( Springer New York ) 199 - 211 2014.01 [Refereed]

DNA methylation and histone modification are epigenetic changes that play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, studies have shown that microRNAs (miRNAs) play important roles in the development of colorectal cancer (CRC), and that epigenetic mechanisms are deeply involved in their dysregulation. Specifically, technological advances that enable comprehensive analysis of miRNA expression profiles and the epigenome in CRC cells have led to the identification of a large number of epigenetically regulated miRNAs. As with protein-coding genes, it appears that miRNA genes involved in regulating cancer-related pathways are silenced in association with CpG island hypermethylation and altered histone modification. Aberrant DNA methylation of miRNA genes is a potentially useful biomarker for detecting CRC or predicting its outcome. Moreover, re-expression of the miRNAs could be an effective approach to cancer therapy, and unraveling the relationship between epigenetic alteration and miRNA dysregulation may lead to the discovery of new therapeutic targets.

HER2 Expression and PI3K-Akt Pathway Alterations in Gastric Cancer

Yasutaka Sukawa, Hiroyuki Yamamoto, Katsuhiko Nosho, Miki Ito, Hisayoshi Igarashi, Takafumi Naito, Kei Mitsuhashi, Yasutaka Matsunaga, Taiga Takahashi, Masashi Mikami, Yasushi Adachi, Hiromu Suzuki, Yasuhisa Shinomura

DIGESTION ( KARGER ) 89 ( 1 ) 12 - 17 2014 [Refereed]

The anti-HER2 antibody trastuzumab has led to an era of personalized therapy in gastric cancer (GC). As a result, HER2 expression has become a major concern in GC. HER2 overexpression is seen in 7-34% of GC cases. Trastuzumab is an antibody that targets the HER2 extracellular domain and induces antibody-dependent cellular cytotoxicity and inhibition of the HER2 downstream signals. Mechanisms of resistance to trastuzumab have been reported in breast cancer. There are various mechanisms underlying trastuzumab resistance, such as alterations of HER2 structure or surroundings, dysregulation of HER2 downstream signal effectors and interaction of HER2 with other membrane receptors. The PI3K-Akt pathway is one of the main downstream signaling pathways of HER2. It is well known that PIK3CA mutations and phosphate and tensin homolog (PTEN) inactivation cause over-activation of the downstream signal without an upstream signal activation. Frequencies of PIK3CA mutations and PTEN inactivation have been reported to be 4-25 and 16-77%, respectively. However, little is known about the association between HER2 expression and PI3K-Akt pathway alterations in GC. We have found that HER2 overexpression was significantly correlated with pAkt expression in GC tissues. Furthermore, pAkt expression was correlated with poor prognosis. These results suggest that the PI3K-Akt pathway plays an important role in HER2-positive GC. Moreover, PIK3CA mutations and/or PTEN inactivation might affect the effectiveness of HER2-targeting therapy. Hence, it is necessary to clarify not only HER2 alterations but also PI3K-Akt pathway alterations for HER2-targeting therapy in GC. This review will introduce recent investigations and consider the current status of HER2-targeted therapy for treatment of GC. (C) 2014 S. Karger AG, Basel

AKR1B10, a Transcriptional Target of p53, Is Downregulated in Colorectal Cancers Associated with Poor Prognosis

Tomoko Ohashi, Masashi Idogawa, Yasushi Sasaki, Hiromu Suzuki, Takashi Tokino

MOLECULAR CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 11 ( 12 ) 1554 - 1563 2013.12 [Refereed]

p53 is one of the most important tumor suppressor genes, and it is frequently inactivated in various cancers. p53 modulates various cellular functions, such as apoptosis and cell-cycle arrest via transcriptional regulation. Recently, p53 has been reported to be involved in a wide range of cellular metabolic pathways, including glycolysis, oxidative phosphorylation, glutaminolysis, and the antioxidant response. To understand the functional mechanism of p53, it is important to find out the direct transcriptional targets of p53. In this study, aldo-keto reductase family 1, member B10 (AKR1B10) was identified as a direct target of the p53 family by cDNA microarray analysis after comparing the mRNA expression of control and H1299 cells that overexpressed with p53 family members. In addition, we found that the expression of AKR1B10 was significantly decreased in colorectal cancers and adenomas as compared with normal colon tissues. Knockdown of AKR1B10 significantly inhibited p53-induced apoptosis in colorectal cancer cells, whereas the overexpression of AKR1B10 enhanced p53-induced apoptosis and inhibited tumor proliferation in vivo. Furthermore, low expression of AKR1B10 in colon cancer patients was correlated with decreased survival and poor prognosis. These results suggest that decreased expression of AKR1B10 could disrupt the tumor suppressive function of p53, which result in decreased survival in colorectal cancer patients. In summary, AKR1B10 may be a novel prognostic predictor and a novel therapeutic target for colorectal cancer. Implications: AKR1B10, a transcriptional target of p53, is also a novel prognostic and therapeutic molecule in colorectal cancer. (C) 2013 AACR.

RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients

Shohei Honda, Hisayuki Miyagi, Hiromu Suzuki, Masashi Minato, Masayuki Haruta, Yasuhiko Kaneko, Kanako C. Hatanaka, Eiso Hiyama, Takehiko Kamijo, Tadao Okada, Akinobu Taketomi

PEDIATRIC SURGERY INTERNATIONAL ( SPRINGER ) 29 ( 11 ) 1147 - 1152 2013.11 [Refereed]

The RAS association domain family protein 1 (RASSF1A) is known to be frequently inactivated by promoter hypermethylation in cancers. This study investigated the association of RASSF1A methylation with clinical outcomes in hepatoblastoma patients and whether it is correlated with the histological phenotype of hepatoblastoma tumors. Seventy-four hepatoblastoma tumors were obtained from patients enrolled in the Japanese study group for pediatric liver tumor protocol-2. From nine formalin-fixed, paraffin-embedded specimens, we extracted DNA by dissection under a light microscope. We examined the methylation status of the RASSF1A promoter region by bisulfite pyrosequencing. Twenty-five (33.8 %) hepatoblastoma tumors were classified as having methylated RASSF1A. The RASSF1A methylation was significantly associated with metastatic tumors and a poor prognosis. Despite the complete resection, five pretreatment extent of disease II tumors showed recurrence or distant metastasis postoperatively. Among these cases, four tumors were found to show RASSF1A methylation. When compared to histologically different types of cell, RASSF1A methylation values in samples of the normal liver, fetal type, and embryonal type, were significantly elevated in ascending order. We confirmed that RASSF1A methylation is a significant prognostic indicator in hepatoblastomas, and it may become a promising molecular marker to stratify patients into appropriate risk groups.

ゲノム網羅的p53結合領域解析によるp53ファミリーの転写標的となる大型介在性非コードRNA(LincRNA)の同定と機能解析(Identification of large intergenic non-coding RNAs regulated by p53 through a genome-wide analysis of p53 binding sites)

井戸川雅史, 大箸智子, 佐々木泰史, 丸山玲緒, 鈴木拓, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 72回 104 - 104 2013.10

p53によるXPO1の抑制機構とその意義(p53 negatively regulates the expression of the nuclear export protein XPO1, establishing a positive feedback loop)

佐々木泰史, 田村みゆき, 竹田康佑, 井戸川雅史, 丸山玲緒, 鈴木拓, 篠村恭久, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 72回 105 - 105 2013.10

食道癌におけるIGF-I受容体の発現と分子標的としての可能性(Insulin-like growth factor-I receptor(IGF-IR) in human esophageal carcinoma: the possibility as its molecular targeting)

松永康孝, 足立靖, 山本博幸, 大橋広和, 能正勝彦, 谷口博昭, 鈴木拓, 佐々木泰史, 有村佳昭, 遠藤高夫, 今井浩三, 篠村恭久

日本癌学会総会記事 ( (一社)日本癌学会 ) 72回 156 - 156 2013.10

Methylation of a Panel of MicroRNA Genes Is a Novel Biomarker for Detection of Bladder Cancer

Takashi Shimizu, Hiromu Suzuki, Masanori Nojima, Hiroshi Kitamura, Eiichiro Yamamoto, Reo Maruyama, Masami Ashida, Tomo Hatahira, Masahiro Kai, Naoya Masumori, Takashi Tokino, Kohzoh Imai, Taiji Tsukamoto, Minoru Toyota

EUROPEAN UROLOGY ( ELSEVIER SCIENCE BV ) 63 ( 6 ) 1091 - 1100 2013.06 [Refereed]

Background: Dysregulation of microRNAs (miRNAs) has been implicated in bladder cancer (BCa), although the mechanism is not fully understood. Objective: We aimed to explore the involvement of epigenetic alteration of miRNA expression in BCa. Design, setting, and participants: Two BCa cell lines (T24 and UM-UC-3) were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which their miRNA expression profiles were analyzed using a TaqMan array (Life Technologies, Carlsbad, CA, USA). Bisulfite pyrosequencing was used to assess miRNA gene methylation in 5 cancer cell lines, 83 primary tumors, and 120 preoperative and 47 postoperative urine samples. Outcome measurements and statistical analysis: Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of the miRNA gene panel. Results and limitations: Of 664 miRNAs examined, 146 were upregulated by 5-aza-dC plus PBA. CpG islands were identified in the proximal upstream of 23 miRNA genes, and 12 of those were hypermethylated in cell lines. Among them, miR-137, miR-124-2, miR-124-3, and miR-9-3 were frequently and tumor-specifically methylated in primary cancers (miR-137: 68.7%; miR-124-2: 50.6%; miR-124-3: 65.1%; miR-9-3: 45.8%). Methylation of the same four miRNAs in urine specimens enabled BCa detection with 81% sensitivity and 89% specificity; the area under the ROC curve was 0.916. Ectopic expression of silenced miRNAs in BCa cells suppressed growth and cell invasion. Conclusions: Our results indicate that epigenetic silencing of miRNA genes may be involved in the development of BCa and that methylation of miRNA genes could be a useful biomarker for cancer detection. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Brush border myosin Ia inactivation in gastric but not endometrial tumors

Rocco Mazzolini, Paulo Rodrigues, Sarah Bazzocco, Higinio Dopeso, Ana M. Ferreira, Silvia Mateo-Lozano, Elena Andretta, Stefan M. Woerner, Hafid Alazzouzi, Stefania Landolfi, Javier Hernandez-Losa, Irati MacAya, Hiromu Suzuki, Santiago Ramõn Y Cajal, Mark S. Mooseker, John M. Mariadason, Johannes Gebert, Robert M.W. Hofstra, Jaume Reventõs, Hiroyuki Yamamoto, Simo Schwartz Jr., Diego Arango

International Journal of Cancer 132 ( 8 ) 1790 - 1799 2013.04 [Refereed]

Brush border Myosin Ia (MYO1A) has been shown to be frequently mutated in colorectal tumors with microsatellite instability (MSI) and to have tumor suppressor activity in intestinal tumors. Here, we investigated the frequency of frameshift mutations in the A8 microsatellite in exon 28 of MYO1A in MSI gastric and endometrial tumors and found a high mutation rate in gastric (22/47 46.8%) but not endometrial (3/48 6.2%) tumors. Using a regression model, we show that MYO1A mutations are likely to confer a growth advantage to gastric, but not endometrial tumors. The mutant MYO1A7A protein was shown to lose its membrane localization in gastric cancer cells and a cycloheximide-chase assay demonstrated that the mutant MYO1A7A protein has reduced stability compared to the wild type MYO1A. Frequent MYO1A promoter hypermethylation was also found in gastric tumors. Promoter methylation negatively correlates with MYO1A mRNA expression in a series of 58 non-MSI gastric primary tumors (Pearson's r = -0.46 p = 0.0003) but not in a cohort of 54 non-MSI endometrial tumors and treatment of gastric cancer cells showing high MYO1A promoter methylation with the demethylating agent 5-aza-2′- deoxycytidine, resulted in a significant increase of MYO1A mRNA levels. We found that normal gastric epithelial cells, but not normal endometrial cells, express high levels of MYO1A. Therefore, when considered together, our findings suggest that MYO1A has tumor suppressor activity in the normal gastric epithelium but not in the normal endometrium and inactivation of MYO1A either genetically or epigenetically may confer gastric epithelial cells a growth advantage. What's new? Brushborder myosin 1A (MYO1A), a monomeric ATP-dependent motor protein, was recently associated with tumor suppressor activity in the colon. Here, the authors demonstrate that MYO1A is one of the most frequently mutated genes (47%) in gastric tumors with microsatellite instability (MSI). Moreover, the promoter of MYO1A was found frequently methylated. This was unique to gastric tumors, as only background mutation rates in MYO1A (6%) were observed in endometrial tumors with MSI, highlighting profound differences in the tumorigenic processes of these organs. Copyright © 2012 UICC.

DNA methyltransferase 1 is essential for initiation of the colon cancers

Rena Morita, Yoshihiko Hirohashi, Hiromu Suzuki, Akari Takahashi, Yasuaki Tamura, Takayuki Kanaseki, Hiroko Asanuma, Satoko Inoda, Toru Kondo, Satoshi Hashino, Tadashi Hasegawa, Takashi Tokino, Minoru Toyota, Masahiro Asaka, Toshihiko Torigoe, Noriyuki Sato

EXPERIMENTAL AND MOLECULAR PATHOLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 94 ( 2 ) 322 - 329 2013.04 [Refereed]

DNA methyltransferase 1 (Dnmt1) is essential for the maintenance of hematopoietic and somatic stem cells in mice; however, its roles in human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are still elusive. In the present study, we investigated DNMT1 functions in the maintenance of human colon CSCs/CICs using the human colon cancer cell line HCT116 (HCT116 w/t) and its DNMT1 knockout cell line (DNMT1(-/-)). The rates of CSCs/CICs were evaluated by side population (SP) analysis, ALDEFLUOR assay and expression of CD44 and CD24. SP, ALDEFLUOR-positive (ALDEFLUOR(+)) and CD44-positive and CD24-positive (CD44(+)CD24(+)) cell rates were lower in DNMT1(-/-) cells than in HCT116 w/t cells. Since CSCs/CICs have higher tumor-initiating ability than that of non-CSCs/CICs, the tumor-initiating abilities were addressed by injecting immune deficient (NOD/SCID) mice. DNMT1(-/-) cells showed less tumor-initiating ability than did HCT116 w/t cells, whereas the growing rate of DNMT1(-/-) cells showed no significant difference from that of HCT116 cells both in vitro and in vivo. Similar results were obtained for cells in which DNMT1 had been transiently knocked-down using gene-specific siRNAs. Taken together, these results indicate that DNMT1 is essential for maintenance of colon CSCs/CICs and that short-term suppression of DNMT1 might be sufficient to disrupt CSCs/CICs. (C) 2012 Elsevier Inc. All rights reserved.

Spontaneous rupture of an advanced pancreatoblastoma: aberrant RASSF1A methylation and CTNNB1 mutation as molecular genetic markers.

Shohei Honda, Tadao Okada, Hisayuki Miyagi, Masatsugu Minato, Hiromu Suzuki, Akinobu Taketomi

Journal of pediatric surgery 48 ( 4 ) e29-32 - 32 2013.04 [Refereed] [International journal]

Cancer detection by ubiquitin carboxyl-terminal esterase L1 methylation in pancreatobiliary fluids

Norihiro Kato, Hiroyuki Yamamoto, Yasushi Adachi, Hirokazu Ohashi, Hiroaki Taniguchi, Hiromu Suzuki, Mayumi Nakazawa, Hiroyuki Kaneto, Shigeru Sasaki, Kohzoh Imai, Yasuhisa Shinomura

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBLISHING GROUP INC ) 19 ( 11 ) 1718 - 1727 2013.03 [Refereed]

AIM: To evaluate the utility of measuring epigenetic alterations in pancreatic and biliary fluids in determining molecular markers for pancreatobiliary cancers. METHODS: DNA was extracted from undiluted pancreatic and biliary fluids. As a surrogate for a genome-wide hypomethylation assay, levels of long interspersed nuclear element-1 (LINE-1) methylation were analyzed using bisulfite pyrosequencing. CpG island hypermethylation of 10 tumor-associated genes, aryl-hydrocarbon receptor repressor, adenomatous polyposis coli, calcium channel, voltage dependent, T type alpha 1G subunit, insulin-like growth factor 2, O-6-methyl-guanine-DNA methyltransferase, neurogenin 1, CDKN2A, runt-related transcription factor 3 (RUNX3), secreted frizzled-related protein 1, and ubiquitin carboxyl-terminal esterase L1 (UCHL1), was analyzed using MethyLight. To examine the role of CpG methylation and histone deacetylation in the silencing of UCHL1, human gallbladder carcinoma cell lines and pancreatic carcinoma cell lines were treated with 2 or 5 mu mol/L 5-AZA-dC for 72 h or 100 nmol/L Trichostatin A for 24 h. After the treatment, UCHL1 expression was analyzed by real-time reverse transcription-polymerase chain reaction. RESULTS: Pancreatobiliary cancers exhibited significantly lower LINE-1 methylation levels in pancreatic and biliary fluids than did noncancerous pancreatobiliary disease (58.7% +/- 4.3% vs 61.7% +/- 2.2%, P = 0.027; 53.8% +/- 6.6% vs 57.5% +/- 1.7%, P = 0.007); however, LINE-1 hypomethylation was more evident in pancreatic cancer tissues than in pancreatic fluids (45.4% +/- 5.5% vs 58.7% +/- 4.3%, P < 0.001). CpG island hypermethylation of tumor-associated genes was detected at various frequencies, but it was not correlated with LINE-1 hypomethylation. Hypermethylation of the UCHL1 gene was cancer-specific and most frequently detected in pancreatic (67%) or biliary (70%) fluids from patients with pancreatobiliary cancer. As a single marker, hypermethylation of the UCHL1 gene in pancreatic and biliary fluids was most useful for the detection of pancreatic and pancreatobiliary cancers, respectively (100% specificity). Hypermethylation of the UCHL1 and RUNX3 genes in pancreatic and biliary fluids was the most useful combined marker for pancreatic (87% sensitivity and 100% specificity) and pancreatobiliary (97% sensitivity and 100% specificity) cancers. Treatment with a demethylating agent, 5-AZA-2'-deoxycytidine, restored UCHL1 expression in pancreatobiliary cancer cell lines. CONCLUSION: Our results suggest that hypermethylation of UCHL1 and RUNX3 in pancreatobiliary fluid might be useful for the diagnosis of pancreatobiliary cancers. (C) 2013 Baishideng. All rights reserved.

Association between genomic alterations and metastatic behavior of colorectal cancer identified by array-based comparative genomic hybridization

Takeshi Sawada, Eiichiro Yamamoto, Hiromu Suzuki, Masanori Nojima, Reo Maruyama, Yoshihiro Shioi, Risaburo Akasaka, Seiko Kamimae, Taku Harada, Masami Ashida, Masahiro Kai, Yasushi Adachi, Hiroyuki Yamamoto, Kohzoh Imai, Minoru Toyota, Fumio Itoh, Tamotsu Sugai

GENES CHROMOSOMES & CANCER ( WILEY ) 52 ( 2 ) 140 - 149 2013.02 [Refereed]

Colorectal cancers (CRCs) exhibit multiple genetic alterations, including allelic imbalances (copy number alterations, CNAs) at various chromosomal loci. In addition to genetic aberrations, DNA methylation also plays important roles in the development of CRC. To better understand the clinical relevance of these genetic and epigenetic abnormalities in CRC, we performed an integrative analysis of copy number changes on a genome-wide scale and assessed mutations of TP53, KRAS, BRAF, and PIK3CA and DNA methylation of six marker genes in single glands isolated from 39 primary tumors. Array-based comparative genomic hybridization (array-CGH) analysis revealed that genomic losses commonly occurred at 3q26.1, 4q13.2, 6q21.32, 7q34, 8p12-23.3, 15qcen and 18, while gains were commonly found at 1q21.3-23.1, 7p22.3-q34, 13q12.11-14.11, and 20. The total numbers and lengths of the CNAs were significantly associated with the aberrant DNA methylation and Dukes' stages. Moreover, hierarchical clustering analysis of the array-CGH data suggested that tumors could be categorized into four subgroups. Tumors with frequent DNA methylation were most strongly enriched in subgroups with infrequent CNAs. Importantly, Dukes' D tumors were enriched in the subgroup showing the greatest genomic losses, whereas Dukes' C tumors were enriched in the subgroup with the greatest genomic gains. Our data suggest an inverse relationship between chromosomal instability and aberrant methylation and a positive association between genomic losses and distant metastasis and between genomic gains and lymph node metastasis in CRC. Therefore, DNA copy number profiles may be predictive of the metastatic behavior of CRCs. (c) 2012 Wiley Periodicals, Inc.

Epigenetic alteration and microRNA dysregulation in cancer

Hiromu Suzuki, Reo Maruyama, Eiichiro Yamamoto, Masahiro Kai

Frontiers in Genetics 4 258 2013 [Refereed]

MicroRNAs (miRNAs) play pivotal roles in numerous biological processes, and their dysregulation is a common feature of human cancer. Thanks to recent advances in the analysis of the cancer epigenome, we now know that epigenetic alterations, including aberrant DNA methylation and histone modifications, are major causes of miRNA dysregulation in cancer. Moreover, the list of miRNA genes silenced in association with CpG island hypermethylation is rapidly growing, and various oncogenic miRNAs are now known to be upregulated via DNA hypomethylation. Histone modifications also play important roles in the dysregulation of miRNAs, and histone deacetylation and gain of repressive histone marks are strongly associated with miRNA gene silencing. Conversely, miRNA dysregulation is causally related to epigenetic alterations in cancer. Thus aberrant methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Given that many of the silenced miRNAs appear to act as tumor suppressors through the targeting of oncogenes, re-expression of the miRNAs could be an effective approach to cancer therapy, and unraveling the relationship between epigenetic alteration and miRNA dysregulation may lead to the discovery of new therapeutic targets. © 2013 Suzuki, Maruyama, Yamamoto and Kai.

Gastric cancers with microsatellite instability sharing clinical features, chemoresistance and germline MSH6 variants

Kentaro Yamashita, Yoshiaki Arimura, Mayuko Saito, Hiromu Suzuki, Tomohisa Furuhata, Koichi Hirata, Yasuhisa Shinomura

Clinical Journal of Gastroenterology ( Springer-Verlag Tokyo ) 6 ( 2 ) 122 - 126 2013 [Refereed]

Recent studies suggest that colorectal cancer with microsatellite instability (MSI) might be resistant to fluorouracil-based chemotherapy however, little is known about the clinical significance of MSI analysis for gastric cancer. We therefore conducted a prospective single center study analyzing MSI in gastric cancer. Of 123 consecutive gastric cancers analyzed, 12 (9.8 %) were MSI-positive and two patients with MSI-positive gastric cancer underwent systemic chemotherapy because of unresectable disease. Neither cases had concurrent nor past history of other malignancies but one had cancer family history meeting the revised Bethesda criteria. These two MSI-positive gastric cancers shared multiple clinical features, such as direct invasion to adjacent organs, extensive nodal metastasis but no distant metastasis, resistance to fluorouracil and death of tumor bleeding. The two cases had unmethylated MLH1 promoter, suggestive of Lynch syndrome. Germline mutation analysis demonstrated MSH6 alterations of unknown significance in both cases. © Springer 2013.

　 PREV - NEXT 　

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

To the head of this page.▲