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PubMed | National Cancer Center Research Institute, National Cancer Center Hospital, Clinical Pathology Laboratories, Mitsui Knowledge Industry Co. and Keio University
Type: | Journal: Carcinogenesis | Year: 2017

The aim of this study was to clarify the significance of DNA methylation alterations shared by cancers derived from multiple organs. We analyzed single-institutional methylome data by single-CpG-resolution Infinium assay for 1,007 samples of non-cancerous tissue (N) and corresponding cancerous tissue (T) obtained from lung, stomach, kidney, breast and liver. Principal component analysis revealed that N samples of each organ showed distinct DNA methylation profiles, DNA methylation profiles of N samples of each organ being inherited by the corresponding T samples and DNA methylation profiles of T samples being more similar to those of N samples in the same organ than those of T samples in other organs. In contrast to such organ and/or carcinogenetic factor-specificity of DNA methylation profiles, when compared to the corresponding N samples, 231 genes commonly showed DNA hypermethylation in T samples in four or more organs. Gene ontology enrichment analysis showed that such commonly methylated genes were enriched among transcriptional factors participating in development and/or differentiation, which reportedly show bivalent histone modification in embryonic stem cells. Pyrosequencing and quantitative reverse transcription-PCR revealed an inverse correlation between DNA methylation levels and mRNA expression levels of representative commonly methylated genes, such as ALX1, ATP8A2, CR1 and EFCAB1, in tissue samples. These data suggest that disruption of the differentiated state of precancerous cells via alterations of expression, independent of differences in organs and/or carcinogenetic factors, may be a common feature of DNA methylation alterations during carcinogenesis in multiple organs.


Yamanoi K.,National Cancer Center Research Institute | Yamanoi K.,Keio University | Arai E.,National Cancer Center Research Institute | Tian Y.,National Cancer Center Research Institute | And 11 more authors.
Carcinogenesis | Year: 2015

The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (βN) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which βN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (βT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, βT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that βT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome. © The Author 2015. Published by Oxford University Press.


Sato M.,Yokohama City University | Sato M.,Japan National Institute of Advanced Industrial Science and Technology | Sato M.,Mitsui Knowledge Industry Co. | Hirokawa T.,Japan National Institute of Advanced Industrial Science and Technology
Journal of Chemical Information and Modeling | Year: 2014

G-protein-coupled receptors (GPCRs) are a pharmaceutically important protein family because they mediate numerous physiological functions. The crystal structures of several GPCR subtypes have been determined recently, encouraging efforts to apply structure-based virtual screening (SBVS) along with ligand-based virtual screening (LBVS) to improve the hit rate of active ligands from large chemical libraries. Three-dimensional models are also necessary for GPCR targets whose structures are unknown. Current challenges include the selection of structural templates from available structurally known GPCRs to use for accurate modeling and understanding the diversity of sites recognizing distinct ligands. We have developed and validated an extended template-based modeling and evaluation method for SBVS. Models were generated using a fragmental template procedure in addition to typical template-based modeling methods. The reliability of the models was evaluated using a virtual screening test with known active ligands and decoys and the consensus of the binding mode using the protein-ligand interaction fingerprint (PLIF) derived from the results of docking simulations. This novel workflow was applied to three targets with known structures (human dopamine receptor 3, human histamine H1 receptor, and human delta opioid receptor) and to a target with an unknown structure (human serotonin 2A receptor). In each case, model structures having high ligand selectivity with consensus binding mode were generated. (Figure Presented) © 2014 American Chemical Society.


Sato T.,National Cancer Center Research Institute | Sato T.,Keio University | Arai E.,National Cancer Center Research Institute | Kohno T.,National Cancer Center Research Institute | And 7 more authors.
International Journal of Cancer | Year: 2014

The aim of this study was to clarify the significance of DNA methylation alterations during lung carcinogenesis. Infinium assay was performed using 139 paired samples of non-cancerous lung tissue (N) and tumorous tissue (T) from a learning cohort of patients with lung adenocarcinomas (LADCs). Fifty paired N and T samples from a validation cohort were also analyzed. DNA methylation alterations on 1,928 probes occurred in N samples relative to normal lung tissue from patients without primary lung tumors, and were inherited by, or strengthened in, T samples. Unsupervised hierarchical clustering using DNA methylation levels in N samples on all 26,447 probes subclustered patients into Cluster I (n = 32), Cluster II (n = 35) and Cluster III (n = 72). LADCs in Cluster I developed from the inflammatory background in chronic obstructive pulmonary disease (COPD) in heavy smokers and were locally invasive. Most patients in Cluster II were non-smokers and had a favorable outcome. LADCs in Cluster III developed in light smokers were most aggressive (frequently showing lymphatic and blood vessel invasion, lymph node metastasis and an advanced pathological stage), and had a poor outcome. DNA methylation levels of hallmark genes for each cluster, such as IRX2, HOXD8, SPARCL1, RGS5 and EI24, were again correlated with clinicopathological characteristics in the validation cohort. DNA methylation profiles reflecting carcinogenetic factors such as smoking and COPD appear to be established in non-cancerous lung tissue from patients with LADCs and may determine the aggressiveness of tumors developing in individual patients, and thus patient outcome. What's new? While genetic abnormalities are well studied in human cancers, epigenetic changes, especially in the early stages of carcinogenesis, remain largely unknown. Here, the authors perform a genome-wide analysis focusing on DNA methylation profiles in "normal" lung tissue adjacent to lung adenocarcinomas. Using single-CpG-resolution Infinium assays, they identify distinct DNA methylation profiles clustering with specific risk factors such as cigarette smoking, inflammation and chronic obstructive pulmonary disease. The authors speculate that these epigenetic profiles detected in the neighboring cells may influence the aggressiveness of tumors developing in individual patients and may thus help predict disease outcome. © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.


Shiota T.,Monash University | Shiota T.,Nagoya University | Imai K.,Japan National Institute of Advanced Industrial Science and Technology | Qiu J.,Albert Ludwigs University of Freiburg | And 19 more authors.
Science | Year: 2015

Mitochondria fulfill central functions in cellular energetics, metabolism, and signaling.The outer membrane translocator complex (the TOM complex) imports most mitochondrial proteins, but its architecture is unknown. Using a cross-linking approach, we mapped the active translocator down to single amino acid residues, revealing different transport paths for preproteins through the Tom40 channel. An N-terminal segment of Tom40 passes from the cytosol through the channel to recruit chaperones from the intermembrane space that guide the transfer of hydrophobic preproteins. The translocator contains three Tom40 β-barrel channels sandwiched between a central α-helical Tom22 receptor cluster and external regulatory Tom proteins. The preprotein-translocating trimeric complex exchanges with a dimeric isoform to assemble new TOM complexes. Dynamic coupling of a-helical receptors, β-barrel channels, and chaperones generates a versatile machinery that transports about 1000 different proteins.


PubMed | Japan National Institute of Advanced Industrial Science and Technology, Mitsui Knowledge Industry Co. and RIKEN
Type: Journal Article | Journal: Journal of chemical information and modeling | Year: 2016

Accurate prediction of binding affinities of drug candidates to their targets remains challenging because of protein flexibility in solution. Conformational flexibility of the ATP-binding site in the CDK2 and ERK2 kinases was identified using molecular dynamics simulations. The binding free energy (G) of twenty-four ATP-competitive inhibitors toward these kinases was assessed using an alchemical free energy perturbation method, MP-CAFEE. However, large calculation errors of 2-3 kcal/mol were observed using this method, where the free energy simulation starts from a single equilibrated conformation. Here, we developed a new G computation method, where the starting structure was set to multiconformations to cover flexibility. The calculation accuracy was successfully improved, especially for larger molecular size compounds, leading to reliable prediction of a broader range of drug candidates. The present study demonstrates that conformational flexibility of interactions between a compound and the glycine-rich loop in the kinases is a key factor in G estimation.


Trademark
Mitsui Knowledge Industry Co. | Date: 2013-09-03

Computer software mainly used for scientific and medical research and analysis. Providing computer software mainly used for scientific and medical research and analysis; Design, development, maintenance, update and configuration setting of computer software mainly used for scientific and medical research and analysis; Design, development and maintenance of computer systems for scientific and medical research and analysis.


PubMed | National Cancer Center Research Institute, National Cancer Center Hospital, Clinical Pathology Laboratories, Mitsui Knowledge Industry Co. and Keio University
Type: Comparative Study | Journal: Carcinogenesis | Year: 2015

The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (N) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which N characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (T) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, T was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that T was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome.


PubMed | National Cancer Center Research Institute, National Cancer Center Hospital, Hitachi Ltd., National Health Research Institute and 2 more.
Type: Journal Article | Journal: International journal of cancer | Year: 2015

CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP-positive renal carcinogenesis. Genome (whole-exome and copy number), transcriptome and proteome (two-dimensional image converted analysis of liquid chromatography-mass spectrometry) analyses were performed using tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and corresponding specimens of non-cancerous renal cortex. Genes encoding microtubule-associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non-synonymous single-nucleotide mutations and insertions/deletions) in CIMP-positive RCCs, whereas CIMP-negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP-positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the The metaphase checkpoint (p = 1.427 10(-6)), Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 10(-6)) and Spindle assembly and chromosome separation (p = 9.260 10(-6)) pathways. Quantitative RT-PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP-positive than in CIMP-negative RCCs. All CIMP-positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP-positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP-positive RCCs.


Matsuoka Y.,The Systems Biology Institute | Ghosh S.,The Systems Biology Institute | Kikuchi N.,Mitsui Knowledge Industry Co. | Kitano H.,The Systems Biology Institute | And 2 more authors.
Bioinformatics | Year: 2010

Summary: Payao is a community-based, collaborative web service platform for gene-regulatory and biochemical pathway model curation. The system combines Web 2.0 technologies and online model visualization functions to enable a collaborative community to annotate and curate biological models. Payao reads the models in Systems Biology Markup Language format, displays them with CellDesigner, a process diagram editor, which complies with the Systems Biology Graphical Notation, and provides an interface for model enrichment (adding tags and comments to the models) for the access-controlled community members. Availability and implementation: Freely available for model curation service at http://www.payaologue.org. Web site implemented in Seaser Framework 2.0 with S2Flex2, MySQL 5.0 and Tomcat 5.5, with all major browsers supported. Contact: kitano@sbi.jp. © The Author 2010. Published by Oxford University Press.

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