Updated on 2022/08/22

写真a

 
KOSEKI Jun
 
Organization
Graduate School of Medicine Center for Neurological Diseases and Cance Associate professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Associate professor

Degree 1

  1. 博士(理学) ( 2010.12   横浜市立大学 ) 

Research Interests 5

  1. 分子構造科学

  2. quantum chemistry

  3. molecular dynamics

  4. in silico drug design

  5. Trans-omics Analysis

Research Areas 3

  1. Life Science / Biophysics

  2. Informatics / Life, health and medical informatics

  3. Nanotechnology/Materials / Fundamental physical chemistry

Research History 10

  1. Nagoya University Graduate School of Medicine   Systems Biology   Associate professor

    2021.4

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    Country:Japan

  2. Nagoya University   Designated associate professor

    2020.1 - 2021.3

  3. 大阪大学大学院医学系研究科   疾患データサイエンス学   特任助教

    2017.4 - 2019.12

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    Country:Japan

  4. 理化学研究所   研究員

    2015.1 - 2016.3

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    Country:Japan

  5. 大阪大学大学院医学系研究科   癌創薬プロファイリング学   特任助教

    2014.4 - 2017.3

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    Country:Japan

  6. 北里大学薬学部   創薬物理化学教室   助教

    2012.4 - 2014.3

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    Country:Japan

  7. 横浜市立大学 国際総合科学研究科   量子物理化学研究室   研究員

    2011.4 - 2020.3

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    Country:Japan

  8. 千葉工業大学   教育センター化学教室   兼任教員

    2011.4 - 2012.3

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    Country:Japan

  9. Kitasato University School of Pharmacy   Physical Chemistry for Drug Design   Designated assistant professor

    2011.4 - 2012.3

  10. 横浜市立大学 国際総合科学研究科   量子物理化学研究室   助手

    2011.1 - 2011.3

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    Country:Japan

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Education 1

  1. Yokohama City University

    2007.4 - 2010.12

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    Country: Japan

Professional Memberships 6

  1. American Association for Cancer Research

  2. THE PHARMACEUTICAL SOCIETY OF JAPAN

  3. THE JAPANESE CANCER ASSOCIATION

  4. THE CHEMICAL SOCIETY OF JAPAN

  5. THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

  6. 情報計算科学生物学会

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Awards 1

  1. Yoshida Prize 2009

    2010.10   Society of Computer Chemistry,Japan   Theoretical Analysis of Molecular Orientational Transition in Solid C60

    Y. Kita, J. Koseki, I. Okada

 

Papers 84

  1. Impact of sarcopenia in patients with advanced or recurrent colorectal cancer treated with regorafenib Reviewed

    Yasushi Murachi, Daisuke Sakai, Jun Koseki, Chiaki Inagaki, Naohiro Nishida, Toshifumi Yamaguchi, Taroh Satoh

    International Journal of Clinical Oncology   Vol. 26 ( 2 ) page: 409 - 416   2020.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    BACKGROUND: Regorafenib is a key agent for patients with advanced or recurrent colorectal cancer. Sarcopenia represented by skeletal muscle depletion is closely related to frailty and predicts oncological prognoses. We hypothesized that sarcopenia negatively affects the time to treatment failure (TTF) or overall survival (OS) of patients treated with regorafenib. METHODS: We retrospectively reviewed the medical records of all patients treated with regorafenib between May 2013 and April 2019 at our institution. The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography (CT) was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36 cm2/m2 for males and 3.92 cm2/m2 for females). RESULTS: Thirty-four patients were analyzed. The prevalence of sarcopenia was 44.1%. Sarcopenia was significantly associated with poorer OS (median 3.2 vs. 5.3 months, p = 0.031). Less 75% 1-Month Relative Dose Intensity patients experienced significantly shorter TTF and OS than the rest, as did patients receiving total regorafenib dose of < 3360 mg (median 3.1 and 9.4 months, p < 0.001). Multivariate analysis showed that sarcopenia was a significant predictor of prognosis. CONCLUSION: Sarcopenia was a predictive marker of negative outcome for patients with advanced or recurrent colorectal cancer treated with regorafenib. Screening for sarcopenia can be used to identify patients more likely to benefit from regorafenib in routine clinical practice.

    DOI: 10.1007/s10147-020-01805-8

    PubMed

    Other Link: http://link.springer.com/article/10.1007/s10147-020-01805-8/fulltext.html

  2. One-carbon metabolism for cancer diagnostic and therapeutic approaches. Reviewed International journal

    Ayumu Asai, Masamitsu Konno, Jun Koseki, Masateru Taniguchi, Andrea Vecchione, Hideshi Ishii

    Cancer letters   Vol. 470   page: 141 - 148   2020.2

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    Altered metabolism is critical for the rapid and unregulated proliferation of cancer cells; hence the requirement for an abundant source of nucleotides. One characteristic of this metabolic reprogramming is in one-carbon (1C) metabolism, which is particularly noteworthy for its role in DNA synthesis. Various forms of methylation are also noteworthy as they relate to cancer cell survival and proliferation. In recent years, 1C metabolism has received substantial attention for its role in cancer malignancy via these functions. Therefore, therapeutic inhibitors targeting 1C metabolism have been utilized as anticancer drugs. This review outlines the importance of 1C metabolism and its clinical application in cancer. Understanding 1C metabolism could aid the development of novel cancer diagnostic and therapeutic methods.

    DOI: 10.1016/j.canlet.2019.11.023

    PubMed

  3. Theoretical analyses and experimental validation of the effects caused by the fluorinated substituent modification of DNA. Reviewed International journal

    Jun Koseki, Masamitsu Konno, Ayumu Asai, Naohiro Horie, Kenta Tsunekuni, Koichi Kawamoto, Satoshi Obika, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Scientific reports   Vol. 10 ( 1 ) page: 1138 - 1138   2020.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Halogen-modified nucleic acid molecules, such as trifluorothymidine (FTD) and 5-fluorouracil, are widely used in medical science and clinical site. These compounds have a very similar nucleobase structure. It is reported that both of these compounds could be incorporated into DNA. The incorporation of FTD produces highly anti-tumor effect. However, it is not known whether to occur a significant effect by the incorporation of 5-fluorouracil. Nobody knows why such a difference will occur. To understand the reason why there is large differences between trifluorothymidine and 5-fluorouracil, we have performed the molecular dynamics simulations and molecular orbital calculations. Although the active interaction energy between Halogen-modified nucleic acids or and complementary adenine was increased, in only FTD incorporated DNA, more strongly dispersion force interactions with an adjacent base were detected in many thermodynamic DNA conformations. As the results, the conformational changes occur even if it is in internal body temperature. Then the break of hydrogen bonding between FTD and complementary adenine base occur more frequently. The double helix structural destabilization of DNA with FTD is resulted from autoagglutination caused by the bonding via halogen orbitals such as halogen bonding and the general van der Waals interactions such as CH-[Formula: see text], lone pair (LP)-[Formula: see text], and [Formula: see text]-[Formula: see text] interactions. Therefore, it is strongly speculated that such structural changes caused by trifluoromethyl group is important for the anti-tumor effect of FTD alone.

    DOI: 10.1038/s41598-020-57899-7

    PubMed

  4. CD44/CD133-Positive Colorectal Cancer Stem Cells are Sensitive to Trifluridine Exposure. Reviewed International journal

    Kenta Tsunekuni, Masamitsu Konno, Naotsugu Haraguchi, Jun Koseki, Ayumu Asai, Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Scientific reports   Vol. 9 ( 1 ) page: 14861 - 14861   2019.10

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    Cancer stem cells (CSCs) are involved in metastatic colorectal cancer recurrence, but no effective therapy targeting these cells is currently available. Because trifluridine (FTD)/tipiracil therapy is used for refractory colorectal cancer, we sought to determine whether FTD is effective against CSC-like cells. CD44+CD133+ high-expressing and other populations of human DLD-1 colon cancer cells were separately isolated through fluorescence-activated cell sorting. The sphere-forming activity of each population and the anti-sphere-forming effects of FTD and fluorouracil (5-FU) on CD44+CD133+ cells were then measured. CD44+CD133+ DLD-1 cells formed substantially more spheres than other cells. Moreover, treating CD44+CD133+ DLD-1 cells with subtoxic concentrations of FTD (1 µM) inhibited sphere formation, and this was superior to the effect of subtoxic concentrations (1 µM) of 5-FU. The associated inhibition rates for FTD and 5-FU were 58.2% and 26.1%, respectively. Further, CD44+CD133+ DLD-1 cells expressed higher levels of thymidine kinase 1, which is responsible for FTD phosphorylation, than DLD-1 cells, and FTD was incorporated into the DNA of CD44+CD133+ DLD-1 cells. Thus, our data show that FTD treatment is effective against CSC-like cells and might be applied as CSC-targeting chemotherapy for tumor subtypes with high CD44 and CD133 expression.

    DOI: 10.1038/s41598-019-50968-6

    PubMed

  5. Computational analyses for cancer biology based on exhaustive experimental backgrounds Invited Reviewed

    Koseki, J, Konno, M, Ishii, H

    Cancer Drug Resistance: Drug resistance and cancer stem cell   Vol. 2   page: 419 - 427   2019.9

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  6. Distinct methylation levels of mature microRNAs in gastrointestinal cancers. Reviewed International journal

    Masamitsu Konno, Jun Koseki, Ayumu Asai, Akira Yamagata, Teppei Shimamura, Daisuke Motooka, Daisuke Okuzaki, Koichi Kawamoto, Tsunekazu Mizushima, Hidetoshi Eguchi, Shuji Takiguchi, Taroh Satoh, Koshi Mimori, Takahiro Ochiya, Yuichiro Doki, Ken Ofusa, Masaki Mori, Hideshi Ishii

    Nature communications   Vol. 10 ( 1 ) page: 3888 - 3888   2019.8

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    The biological significance of micro (mi)RNAs has traditionally been evaluated according to their RNA expression levels based on the assumption that miRNAs recognize and regulate their targets in an unvarying fashion. Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition. Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity. These findings provide a basis for diagnostic strategies for early-stage cancer and add a dimension to our understanding of miRNA biology.

    DOI: 10.1038/s41467-019-11826-1

    PubMed

  7. A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma. Reviewed International journal

    Katsunori Matsushita, Takumi Okuda, Shohei Mori, Masamitsu Konno, Hidetoshi Eguchi, Ayumu Asai, Jun Koseki, Yoshifumi Iwagami, Daisaku Yamada, Hirofumi Akita, Tadafumi Asaoka, Takehiro Noda, Koichi Kawamoto, Kunihito Gotoh, Shogo Kobayashi, Yuuya Kasahara, Kunihiko Morihiro, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii, Satoshi Obika

    ChemMedChem   Vol. 14 ( 15 ) page: 1384 - 1391   2019.8

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    The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2 O2 concentrations found in cancer cells to release GEM. An H2 O2 -activatable GEM (A-GEM) has higher selectivity for H2 O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2 O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment.

    DOI: 10.1002/cmdc.201900324

    PubMed

  8. Mitochondrial pyruvate carrier 1 expression controls cancer epithelial-mesenchymal transition and radioresistance. Reviewed International journal

    Yuji Takaoka, Masamitsu Konno, Jun Koseki, Hugh Colvin, Ayumu Asai, Keisuke Tamari, Taroh Satoh, Masaki Mori, Yuichiro Doki, Kazuhiko Ogawa, Hideshi Ishii

    Cancer science   Vol. 110 ( 4 ) page: 1331 - 1339   2019.4

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    Mitochondrial pyruvate carrier (MPC) is known to cause different expressions in normal and cancer cells. We observed a change in phenotype with the suppression of MPC expression. We knocked down MPC1 and/or MPC2 using siRNA or shRNA. We observed its cell morphology and accompanying molecular marker. Furthermore, the radioresistance of the MPC knockdown cell line was examined using a colony formation assay. MPC1-suppressed cells changed their morphology to a spindle shape. Epithelial-mesenchymal transition (EMT) was suspected, and examination of the EMT marker by PCR showed a decrease in E-cadherin and an increase in fibronectin. Focusing on glutamine metabolism as the mechanism of this phenomenon, we knocked down the glutamine-metabolizing enzyme glutaminase (GLS). EMT was also observed in GLS-suppressed cells. Furthermore, when MPC1-suppressed cells were cultured in a glutamine-deficient medium, changes in EMT markers were suppressed. In addition, MPC1-suppressed cells also increased with a significant difference in radioresistance. Decreased MPC1 expression favorably affects EMT and radioresistance of cancer.

    DOI: 10.1111/cas.13980

    PubMed

  9. Direct Analysis of Incorporation of an Anticancer Drug into DNA at Single-Molecule Resolution. Reviewed International journal

    Takahito Ohshiro, Yuuki Komoto, Masamitsu Konno, Jun Koseki, Ayumu Asai, Hideshi Ishii, Masateru Taniguchi

    Scientific reports   Vol. 9 ( 1 ) page: 3886 - 3886   2019.3

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    Identifying positions at which anticancer drug molecules incorporate into DNA is essential to define mechanisms underlying their activity, but current methodologies cannot yet achieve this. The thymidine fluorine substitution product trifluridine (FTD) is a DNA-damaging anticancer agent thought to incorporate into thymine positions in DNA. This mechanism, however, has not been directly confirmed. Here, we report a means to detect FTD in a single-stranded oligonucleotide using a method to distinguish single molecules by differences in electrical conductance. Entire sequences of 21-base single-stranded DNAs with and without incorporated drug were determined based on single-molecule conductances of the drug and four deoxynucleosides, the first direct observation of its kind. This methodology may foster rapid development of more effective anticancer drugs.

    DOI: 10.1038/s41598-019-40504-x

    PubMed

  10. Poly(ethylene glycol)-poly(lysine) block copolymer-ubenimex conjugate targets aminopeptidase N and exerts an antitumor effect in hepatocellular carcinoma stem cells. Reviewed International journal

    Reishi Toshiyama, Masamitsu Konno, Hidetoshi Eguchi, Hiroyasu Takemoto, Takehiro Noda, Ayumu Asai, Jun Koseki, Naotsugu Haraguchi, Yuji Ueda, Katsunori Matsushita, Kei Asukai, Tomofumi Ohashi, Yoshifumi Iwagami, Daisaku Yamada, Daisuke Sakai, Tadafumi Asaoka, Toshihiro Kudo, Koichi Kawamoto, Kunihito Gotoh, Shogo Kobayashi, Taroh Satoh, Yuichiro Doki, Nobuhiro Nishiyama, Masaki Mori, Hideshi Ishii

    Oncogene   Vol. 38 ( 2 ) page: 244 - 260   2019.1

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    Previous studies highlighted that aminopeptidase N (APN)/CD13 acts as a scavenger in the survival of hepatocellular carcinoma (HCC) stem cells by reducing reactive oxygen species (ROS) levels. Hence, it has been proposed that APN/CD13 inhibition can increase cellular ROS levels and sensitize cells to chemotherapeutic agents. Although ubenimex, also known as bestatin, competitively inhibits proteases such as APN/CD13 on the cellular membrane and it is clinically used for patients with acute myeloid leukemia and lymphedema, research has demonstrated that higher concentrations of the agent induce the death of APN/CD13+ HCC stem cells. In this study, we developed a poly(ethylene glycol)-poly(lysine) block copolymer-ubenimex conjugate (PEG-b-PLys(Ube)) to increase the efficacy of reagents in APN/CD13+ cancer stem cells. Exposure to PEG-b-PLys(Ube) increased the intracellular ROS concentration by inhibiting APN enzyme activity, permitting the induction of apoptosis and attenuation of HCC cell proliferation. In addition, PEG-b-PLys(Ube) exhibited a relatively stronger antitumor effect in mice than PEG-b-PLys alone or phosphate-buffered saline. Moreover, an isobologram analysis revealed that combinations of fluorouracil, cisplatin, or doxorubicin with PEG-b-PLys(Ube) exhibited synergistic effects. This study demonstrated that PEG-b-PLys(Ube) does not impair the properties of ubenimex and exerts a potent antitumor effect.

    DOI: 10.1038/s41388-018-0406-x

    PubMed

  11. Ability of a convolutional neural network to differentiate between mouse and human cell lines and their radioresistant clones using microscopic images Reviewed

    Toratani, M, Konno, M, Asai, A, Koseki, J, Kawamoto, K, Tamari, K, Li, Z, Sakai, D, Kudo, T, Satoh, T, Sato, K, Motooka, D, Okuzaki, D, Doki, Y, Mori, M, Ogawa, K, Ishii, H

    Cancer Resarch   Vol. 78 ( 23 ) page: 6703 - 6707   2019

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  12. Disruption of endolysosomal RAB5/7 efficiently eliminates colorectal cancer stem cells Reviewed

    Takeda, M, Koseki, J, Takahashi, H, Miyoshi, N, Nishida, N, Nishimura, J, Hata, T, Matsuda, C, Mizushima, T, Yamamoto, H, Ishii, H, Doki, Y, Mori, M, Haraguchi, N

    Cancer Resarch     page: .   2019

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  13. Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2. Reviewed International journal

    Ayumu Asai, Jun Koseki, Masamitsu Konno, Tatsunori Nishimura, Noriko Gotoh, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Heliyon   Vol. 4 ( 12 ) page: e01021 - 17   2018.12

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    Many anticancer drugs have serious adverse effects; therefore, it is necessary to target features specific to cancer cells to minimize the effects on healthy cells. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was reported to be specifically enhanced in cancer. We confirmed the validity of MTHFD2 as a drug discovery target using clinical data. In addition, we performed in silico screening to design an anticancer drug specifically targeting MTHFD2. Analysis of the clinical data indicated that MTHFD2 was enhanced in most cancers compared with normal tissues, and affected the prognosis in cancer patients. Candidate compounds for MTHFD2 inhibitors were identified using in silico drug discovery techniques, and the important interactions for MTHFD2 binding were determined. In addition, these candidate compounds decreased levels of MTHFD2 metabolites in cancer cells. The findings of the present study may help to develop anticancer drugs targeting MTHFD2, with a view to minimizing the adverse effects of anticancer drugs.

    DOI: 10.1016/j.heliyon.2018.e01021

    PubMed

  14. Carbon ion beam radioresistant rodent cells are sensitized to trifluorothymidine exposure. Reviewed International journal

    Sung-Jae Baek, Katsutoshi Sato, Naohiro Nishida, Jun Koseki, Kazuhiko Hayashi, Koichi Kawamoto, Masamitsu Konno, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa, Hideshi Ishii

    Oncology letters   Vol. 16 ( 3 ) page: 3389 - 3393   2018.9

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    Although charged particle therapy, including carbon ion beam radiation, is a cutting-edge technology in human cancer treatment, the molecular mechanisms underlying cellular resistance to this type of therapy remain unknown. Furthermore, the chemotherapeutic agents that are most effective at overcoming cellular resistance remain unknown. In the present study, carbon ion beam radioresistant rodent cells were developed and their sensitization to trifluorothymidine (FTD), a derivative of deoxythymidine, was studied. The results of the present study demonstrated that carbon ion beam radioresistant cells were more sensitive to FTD compared with X-ray radioresistant cells. The results of the present study suggested that FTD is involved in carbon ion beam radioresistance, encouraging further study of cellular resistance to charged particle therapy for refractory human cancer.

    DOI: 10.3892/ol.2018.9004

    PubMed

  15. Cell-free culture conditioned medium elicits pancreatic β cell lineage-specific epigenetic reprogramming in mice. Reviewed International journal

    Koichi Kawamoto, Tomofumi Ohashi, Masamitsu Konno, Naohiro Nishida, Jun Koseki, Hidetoshi Matsui, Daisuke Sakai, Toshihiro Kudo, Hidetoshi Eguchi, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Oncology letters   Vol. 16 ( 3 ) page: 3255 - 3259   2018.9

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    There are several obstacles to overcome prior to achieving cellular reprogramming of pancreatic β cells in vitro and in vivo. The present study demonstrated that the transfer of epigenetic phenotypes was achieved in the cell-free conditioned medium (CM) of pancreatic insulinoma MIN6 cell cultures. The comparison of a subpopulation of MIN6, m14 and m9 cells indicated that MIN6-m14 cells were more prone to cellular reprogramming. Epigenetic profiling revealed that the transcription factor pancreas/duodenum homeobox protein 1 (Pdx1) was differentially associated among the clones. The culture of differentiated adipocytes in the CM of MIN6-m14 cells resulted in the induction of insulin mRNA expression, and was accompanied by epigenetic events of Pdx1 binding. The epigenetic profiling indicated that Pdx1 is preferentially associated with a previously uncharacterized region of the endoplasmic reticulum (ER) disulfide oxidase, ER oxidoreductin 1 gene. Therefore, the results of the present study indicated that the CM of MIN6 cells was able to induce a pancreatic β cell-like phenotype in differentiated adipocytes. These data provide additional support for the utility of cell-free CM for cellular reprogramming.

    DOI: 10.3892/ol.2018.9008

    PubMed

  16. ミトコンドリア・ピルビン酸輸送体は上皮間葉形質転換と放射線抵抗性を制御する(Mitochondrial pyruvate career expression controls epithelial mesenchymal transition and radiation resistance) Reviewed

    高岡 祐史, 今野 雅允, 小関 準, 浅井 歩, 玉利 慶介, 土岐 祐一郎, 森 正樹, 石井 秀始, 小川 和彦

    日本癌学会総会記事   Vol. 77回   page: 1364 - 1364   2018.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:(一社)日本癌学会  

  17. 癌幹細胞の代謝とエピジェネティクスの関係を標的とした創薬(Elucidation of a linkage of cancer metabolism and epigenetic control in cancer stem cells for drug discovery) Reviewed

    玉利 慶介, 今野 雅允, 小関 準, 浅井 歩, 佐藤 太郎, 土岐 祐一郎, 森 正樹, 小川 和彦, 石井 秀始

    日本癌学会総会記事   Vol. 77回   page: 918 - 918   2018.9

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  18. c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer. Reviewed International journal

    Kozo Noguchi, Masamitsu Konno, Hidetoshi Eguchi, Koichi Kawamoto, Ryouta Mukai, Naohiro Nishida, Jun Koseki, Hiroshi Wada, Hirofumi Akita, Taroh Satoh, Shigeru Marubashi, Hiroaki Nagano, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Oncology letters   Vol. 16 ( 2 ) page: 1892 - 1898   2018.8

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    Pancreatic adenocarcinoma is thought to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs), which exhibit similar morphological and genetic features to pancreatic ductal adenocarcinoma (PDAC). Therefore, a better understanding of the biological features underlying the progression of PanIN is essential to development more effective therapeutic interventions for PDAC. In recent years, numerous studies have reported that MET proto-oncogene receptor tyrosine kinase (c-MET) is a potential marker of pancreatic cancer stem cells (CSCs). CSCs have been revealed to initiate and propagate tumors in vitro and in vivo, and are associated with a chemoresistant phenotype. However, in vivo models using a xenograft approach are limited. In the present study, the morphological phenotype, molecular alteration and biological behavior of neoplasia in Pdx-1Cre/+, KrasLSL-G12D/+ and Metflox/flox and wild-type mice was analyzed. The results demonstrated that while oncogenic KrasLSL-G12D/+ increased PanIN initiation and significantly decreased survival rate compared with wild-type mice, no additive effect of c-Met receptor signaling on PanIN progression or prognosis was observed. Following gemcitabine administration, c-Met inhibition in Kras LSL-G12D/+ mice significantly decreased the total surface area of PanIN lesions and the number of anti-proliferation marker protein Ki-67 positive cells occupying PanIN lesions compared with Met+/+ mice. In conclusion, complete inhibition of the c-Met signaling pathway with chemotherapy may be useful for the treatment of pancreatic cancer.

    DOI: 10.3892/ol.2018.8793

    PubMed

  19. The mitochondrial one-carbon metabolic pathway is associated with patient survival in pancreatic cancer. Reviewed International journal

    Kozo Noguchi, Masamitsu Konno, Jun Koseki, Naohiro Nishida, Koichi Kawamoto, Daisaku Yamada, Tadafumi Asaoka, Takehiro Noda, Hiroshi Wada, Kunihito Gotoh, Daisuke Sakai, Toshihiro Kudo, Taroh Satoh, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Oncology letters   Vol. 16 ( 2 ) page: 1827 - 1834   2018.8

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    The expression levels of one-carbon metabolic enzymes were investigated and observed to be correlated with clinicopathological parameters in patients with pancreatic cancer. Mitochondrial one-carbon metabolism comprises a network of biological reactions that integrate nutrient status with nucleotide synthesis, amino acid metabolism, antioxidant reduced nicotinamide adenine dinucleotide phosphate production and epigenetic methylation processes. Previous studies have reported that the hyper-activation of mitochondrial one-carbon metabolism serves a significant role in malignant cancer phenotypes. A total of 103 patients underwent surgical resection of pancreatic ductal adenocarcinomas (PDAC) at Osaka University Hospital between April 2007 and December 2013 and were enrolled in this study. Subsequently, the expression of the one-carbon metabolic enzymes methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), aldehyde dehydrogenase 1 family member L2 (ALDH1L2), and serine hydroxymethyltransferase (SHMT2) was examined using immunohistochemical analysis. The immunohistochemical analyses demonstrated that patients with high expression levels of MTHFD2, ALDH1L2 or SHMT2 had significantly poor overall survival (OS) and disease-free survival (DFS) rates, as compared with patients with low expression levels. Furthermore, multivariate Cox proportional hazards analysis indicated that MTHFD2 and ALDH1L2 were independent prognostic factors for OS and DFS, whereas SHMT2 was not predictive of DFS. However, high and low expression levels of all three folate metabolic enzymes were significantly associated with improved OS and DFS, compared with the high expression of one or two folate metabolic enzymes. The expression levels of mitochondrial one-carbon metabolic enzymes are independent prognostic factors and potential therapeutic targets for future pancreatic cancer treatments.

    DOI: 10.3892/ol.2018.8795

    PubMed

  20. Association of iron metabolic enzyme hepcidin expression levels with the prognosis of patients with pancreatic cancer. Reviewed International journal

    Reishi Toshiyama, Masamitsu Konno, Hidetoshi Eguchi, Ayumu Asai, Takehiro Noda, Jun Koseki, Kei Asukai, Tomofumi Ohashi, Katsunori Matsushita, Yoshifumi Iwagami, Daisaku Yamada, Tadafumi Asaoka, Hiroshi Wada, Koichi Kawamoto, Kunihito Gotoh, Toshihiro Kudo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Oncology letters   Vol. 15 ( 5 ) page: 8125 - 8133   2018.5

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    Hepcidin and ferroportin, which are known as key iron regulators, may be used in future treatments of pancreatic ductal adenocarcinoma. Iron is essential for life support; it helps oxygen molecules bind to hemoglobin and acts as an important catalytic enzyme center. However, iron overload is a risk factor for cancer, possibly through the generation of reactive oxygen species (ROS). Hepcidin, which is a peptide hormone mainly generated by the liver, inhibits iron absorption via enterocytes and iron release from macrophages. Notably, hepcidin regulates iron homeostasis in the body by regulating the iron transporter ferroportin. In the present study, it was assumed that high hepcidin expression and low ferroportin expression result in malignancy. Therefore, it was examined whether hepcidin and ferroportin expression levels were correlated with the prognosis of pancreatic cancer in patients. Results revealed that high hepcidin expression levels and low ferroportin expression levels in pancreatic cancer tissue were significantly associated with poor prognosis in the analyses of overall survival (P=0.0140 and 0.0478, respectively). Additionally, there was no significant difference in disease-free survival in the hepcidin- and ferroportin-staining groups. Hepcidin expression correlated with the pathological stage and vascular invasion (P=0.0493 and 0.0400, respectively), and ferroportin expression was correlated with age (P=0.0372). Multivariate analysis of overall survival in the hepcidin-staining group revealed that pathological N factor (pN), adjuvant chemotherapy, and hepcidin expression were independent prognostic factors (P=0.0450, 0.0002, and 0.0049, respectively). Similarly, multivariate analysis of overall survival in the ferroportin-staining group revealed that vascular invasion, and ferroportin expression were independent prognostic factors (P=0.0028, P<0.0001, and P=0.0056, respectively). Thus, hepcidin and ferroportin expressions might be novel prognostic indicators for pancreatic cancer.

    DOI: 10.3892/ol.2018.8357

    PubMed

  21. Fetal hepatocyte-derived culture medium elicits adipocyte differentiation to bile duct cell lineages in a mouse model. Reviewed International journal

    Hisataka Ogawa, Masamitsu Konno, Koichi Kawamoto, Naohiro Nishida, Jun Koseki, Tsunekazu Mizushima, Taroh Satoh, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Biomedical reports   Vol. 8 ( 5 ) page: 497 - 499   2018.5

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    Fetal cells in the developmental stages function with a distinct mechanism in comparison to adult tissues, which may be a useful source for regenerative medicine in postnatal medicine; however, the precise molecular mechanism remains to be elucidated fully. The present study investigated murine fetal hepatocytes, which were cultured in vitro, and the supernatants were used for the culture with murine adipose tissue-derived cells. Notably, the results indicated that fetal hepatocyte-derived culture medium elicits the induction of differentiation of adipose tissue-derived cells to bile duct cell lineages, but not to hepatocyte lineages in mice. This indicates that fetal cells possess the multi potentials, which are already absent in adults, and may be useful for regenerative medicine in future.

    DOI: 10.3892/br.2018.1080

    PubMed

  22. Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma. Reviewed International journal

    Tomofumi Ohashi, Hidetoshi Eguchi, Koichi Kawamoto, Masamitsu Konno, Ayumu Asai, Hugh Colvin, Yuji Ueda, Hirofumi Takaoka, Yoshifumi Iwagami, Daisaku Yamada, Tadafumi Asaoka, Takehiro Noda, Hiroshi Wada, Kunihito Gotoh, Shogo Kobayashi, Jun Koseki, Taroh Satoh, Kazuhiko Ogawa, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Oncology reports   Vol. 39 ( 3 ) page: 1276 - 1282   2018.3

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    Intrahepatic cholangiocarcinoma (ICC) is known to have a high malignant potential. Because of its high recurrence rate, ICC has a poor prognosis even after complete tumor resection. Compared with normal differentiated cells, cancer cells have an altered metabolism for supporting their survival in severe conditions. Cancer cells acquire additional malignant potential as a result of this metabolic alteration. Thus, the molecules known to be involved in cancer metabolism, could be novel therapeutic targets. The mitochondrial pyruvate carrier (MPC) is a recently discovered pyruvate transporter, which is located in the mitochondrial inner membrane. Although MPC is composed of two subunits, it has been reported that the MPC1 subunit is specifically associated with poor prognosis in several cancers, including colorectal and prostate cancer. However, only a few studies have assessed the clinical significance of MPC1 and the molecular mechanisms underlying its influence on cancer progression are not well understood. This study aimed to clarify the function of MPC1 that affects the malignant potential of ICC. The expression of MPC1 in ICC clinical specimens was determined by immunohistochemistry. In addition, the correlations between MPC1 expression and the survival rate, as well as various clinicopathological parameters were assessed. Low MPC1 expression correlated with poor ICC prognosis and was correlated with tumor invasion and distant metastasis. Both these phenomena are closely associated with the epithelial-mesenchymal transition (EMT). Therefore, we investigated the impact of altering the MPC1 gene expression on the malignant potential of cancer cells using biliary tract cancer cell lines in vitro. The expression of MPC1 was downregulated in the cells induced to undergo EMT following treatment with TGF-β. Furthermore, the inhibition of MPC1 expression induced EMT in cancer cells, and the overexpression of MPC1 suppressed the migration of tumor cells. These results indicated that MPC1 could be a novel therapeutic target in some cancers.

    DOI: 10.3892/or.2017.6172

    PubMed

  23. Hypoxia stimulates the cytoplasmic localization of oncogenic long noncoding RNA LINC00152 in colorectal cancer. Reviewed International journal

    Yujiro Nishizawa, Masamitsu Konno, Ayumu Asai, Jun Koseki, Koichi Kawamoto, Norikatsu Miyoshi, Hidekazu Takahashi, Naohiro Nishida, Naotsugu Haraguchi, Daisuke Sakai, Toshihiro Kudo, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    International journal of oncology   Vol. 52 ( 2 ) page: 453 - 460   2018.2

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    Recent studies have indicated that long noncoding RNAs (lncRNAs) play a pivotal role in almost all physiological cellular processes, including every stage of cancer development. Given that hypoxia in the tumor microenvironment is involved in the malignant behavior of tumors, such as invasion and metastasis, we investigated the cytoplasmic and nuclear localization of lncRNAs in colorectal cancer cells. A cell culture under hypoxic conditions revealed several lncRNAs, such as LINC00152, whose levels were increased in the cytoplasm of colorectal cancer cells. A database study indicated that LINC00152 shares microRNA-binding sites, such as miR-138 and miR-193, with the hypoxia-inducible factor 1 (HIF1), thus suggesting that LINC00152 could possibly function as a competing endogenous RNA that can augment Hif1 translation in the cytoplasm of hypoxic colorectal cancer cells. Moreover, the data presented in the studies of surgically resected samples showed that patients with colorectal cancer exhibiting high LINC00152 expression were associated with a worsened survival rate; this supports the suggested oncogenic function of LINC00152 in the cytoplasm under hypoxic conditions. The present study demonstrated that lncRNA networks could provide diagnostic tools and novel therapeutic targets against colorectal cancer cells.

    DOI: 10.3892/ijo.2017.4218

    PubMed

  24. The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Reviewed International journal

    Kosuke Taketo, Masamitsu Konno, Ayumu Asai, Jun Koseki, Masayasu Toratani, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii, Kazuhiko Ogawa

    International journal of oncology   Vol. 52 ( 2 ) page: 621 - 629   2018.2

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    N6-methyladenosine (m6A) is the most abundant epitranscriptome modification in mammalian mRNA. Recent years have seen substantial progress in m6A epitranscriptomics, indicating its crucial roles in the initiation and progression of cancer through regulation of RNA stabilities, mRNA splicing, microRNA processing and mRNA translation. However, by what means m6A is dynamically regulated or written by enzymatic components represented by methyltransferase-like 3 (METTL3) and how m6A is significant for each of the numerous genes remain unclear. We focused on METTL3 in pancreatic cancer, the prognosis of which is not satisfactory despite the development of multidisciplinary therapies. We established METTL3-knockdown pancreatic cancer cell line using short hairpin RNA. Although morphologic and proliferative changes were unaffected, METTL3-depleted cells showed higher sensitivity to anticancer reagents such as gemcitabine, 5-fluorouracil, cisplatin and irradiation. Our data suggest that METTL3 is a potent target for enhancing therapeutic efficacy in patients with pancreatic cancer. In addition, we performed cDNA expression analysis followed by gene ontology and protein-protein interaction analysis using the Database for Annotation, Visualization, and Integrated Discovery and Search Tool for the Retrieval of Interacting Genes/Proteins databases, respectively. The results demonstrate that METTL3 was associated with mitogen-activated protein kinase cascades, ubiquitin-dependent process and RNA splicing and regulation of cellular process, suggesting functional roles and targets of METTL3.

    DOI: 10.3892/ijo.2017.4219

    PubMed

  25. Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer. Reviewed International journal

    Yujiro Nishizawa, Masamitsu Konno, Ayumu Asai, Jun Koseki, Koichi Kawamoto, Norikatsu Miyoshi, Hidekazu Takahashi, Naohiro Nishida, Naotsugu Haraguchi, Daisuke Sakai, Toshihiro Kudo, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Oncotarget   Vol. 9 ( 7 ) page: 7476 - 7486   2018.1

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    Recent studies that have emerged on the diversity of RNA modification in tumors suggest their eligibility as bona fide targets in diagnosis and drug discovery. N6-methyladenosine (m6A) was first reported and is most common in epitranscriptome modification of various RNAs. The YT521-B homology (YTH) domain family are representative m6A-binding proteins, but how the YTH domain family is involved in cancer remains to be clearly understood. Given that clinical sequence data in colorectal cancer indicate that overexpression of YTHDF1 is outstanding among other family members, we studied the role of Ythdf1 and the transcriptional control of YTHDF1. Immunostaining of Ythdf1 showed that its expression was associated with various malignant tumor behaviors, such as depth, lymph node metastasis, and poorer cancer stages. The study of patient survival indicated that patients with high Ythdf1 expression had significantly poorer overall survival. The results indicated that Ythdf1 expression is an independent prognostic factor of patients. The in vitro study showed that the knockdown of YTHDF1 resulted in the suppression of cancer proliferation and sensitization to the exposure of anticancer drugs such as fluorouracil and oxaliplatin. Importantly, the study upstream of the YTHDF1 gene indicated that an oncogenic transcription factor c-Myc was associated with YTHDF1 in both expression and chromatin immunoprecipitation data. Moreover, the knockdown experiments of c-Myc showed the inhibition of YTHDF1, supporting a notion of c-Myc-driven YTHDF1 axis significance. These data suggest that m6A reader Ythdf1 plays a significant role in colorectal cancer progression.

    DOI: 10.18632/oncotarget.23554

    PubMed

  26. Computational trans-omics approach characterised methylomic and transcriptomic involvements and identified novel therapeutic targets for chemoresistance in gastrointestinal cancer stem cells. Reviewed International journal

    Masamitsu Konno, Hidetoshi Matsui, Jun Koseki, Ayumu Asai, Yoshihiro Kano, Koichi Kawamoto, Naohiro Nishida, Daisuke Sakai, Toshihiro Kudo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Scientific reports   Vol. 8 ( 1 ) page: 899 - 899   2018.1

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    We investigated the relationship between methylomic [5-methylation on deoxycytosine to form 5-methylcytosine (5mC)] and transcriptomic information in response to chemotherapeutic 5-fluorouracil (5-FU) exposure and cisplatin (CDDP) administration using the ornithine decarboxylase (ODC) degron-positive cancer stem cell model of gastrointestinal tumour. The quantification of 5mC methylation revealed various alterations in the size distribution and intensity of genomic loci for each patient. To summarise these alterations, we transformed all large volume data into a smooth function and treated the area as a representative value of 5mC methylation. The present computational approach made the methylomic data more accessible to each transcriptional unit and allowed to identify candidate genes, including the tumour necrosis factor receptor-associated factor 4 (TRAF4), as novel therapeutic targets with a strong response to anti-tumour agents, such as 5-FU and CDDP, and whose significance has been confirmed in a mouse model in vivo. The present study showed that 5mC methylation levels are inversely correlated with gene expression in a chemotherapy-resistant stem cell model of gastrointestinal cancer. This mathematical method can be used to simultaneously quantify and identify chemoresistant potential targets in gastrointestinal cancer stem cells.

    DOI: 10.1038/s41598-018-19284-3

    PubMed

  27. Enzymes of the one-carbon folate metabolism as anticancer targets predicted by survival rate analysis. Reviewed International journal

    Jun Koseki, Masamitsu Konno, Ayumu Asai, Hugh Colvin, Koichi Kawamoto, Naohiro Nishida, Daisuke Sakai, Toshihiro Kudo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Scientific reports   Vol. 8 ( 1 ) page: 303 - 303   2018.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    The significance of mitochondrial metabolism in cancer cells has recently been gaining attention. Among other findings, One-carbon folate metabolism has been reported to be closely associated with cellular characteristics in cancer. To study molecular targets for efficient cancer therapy, we investigated the association between the expressions of genes that code enzymes involved in one-carbon metabolism and survival rate of patients with adenocarcinomas of the colorectum and lung. Patients with high expression of genes that control the metabolic cycle of tetrahydrofolate (THF) in mitochondria, SHMT2, MTHFD2, and ALDH1L2, have a shorter overall survival rate compared with patients with low expression of these genes. Our results revealed that these genes could be novel and more promising anticancer targets than dihydrofolate reductase (DHFR), the current target of drug therapy linked with folate metabolism, suggesting the rationale of drug discovery in cancer medicine.

    DOI: 10.1038/s41598-017-18456-x

    PubMed

  28. The Significance of Histone demethylase NO66 in colorectal cancer development Reviewed

    Nishizawa Yujiro, Nishida Naohiro, Konno Masamitsu, Kawamoto Koichi, Koseki Jun, Asai Ayumu, Nishimura Junichi, Hata Taishi, Matsuda Chu, Mizushima Tsunekazu, Doki Yuichiro, Mori Masaki, Ishii Hideshi

    CANCER SCIENCE   Vol. 109   page: 680   2018.1

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    Web of Science

  29. Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells. Reviewed International journal

    Keisuke Tamari, Masamitsu Konno, Ayumu Asai, Jun Koseki, Kazuhiko Hayashi, Koichi Kawamoto, Noriyuki Murai, Senya Matsufuji, Fumiaki Isohashi, Taroh Satoh, Noriko Goto, Shinji Tanaka, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa, Hideshi Ishii

    Cell death discovery   Vol. 4   page: 104 - 104   2018

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    Cancer stem cells (CSCs) exhibit tumorigenic potential and can generate resistance to chemotherapy and radiotherapy. A labeled ornithine decarboxylase (ODC, a rate-limiting enzyme involved in polyamine [PA] biosynthesis) degradation motif (degron) system allows visualization of a fraction of CSC-like cells in heterogeneous tumor populations. A labeled ODC degradation motif system allowed visualization of a fraction of CSC-like cells in heterogeneous tumor populations. Using this system, analysis of polyamine flux indicated that polyamine metabolism is active in CSCs. The results showed that intracellular polyamines inhibited the activity of histone lysine 4 demethylase enzymes, including lysine-specific demethylase-1 (LSD1). Chromatin immunoprecipitation with Pol II antibody followed by massively parallel DNA sequencing, revealed the global enrichment of Pol II in transcription start sites in CSCs. Increase of polyamines within cells resulted in an enhancement of ID1 gene expression. The results of this study reveal details of metabolic pathways that drive epigenetic control of cancer cell stemness and determine effective therapeutic targets in CSCs.

    DOI: 10.1038/s41420-018-0117-7

    PubMed

  30. Low expression of the GOPC is a poor prognostic marker in colorectal cancer Reviewed

    Nobuyoshi Ohara, Naotsugu Haraguchi, Jun Koseki, Yujiro Nishizawa, Kenji Kawai, Hidekazu Takahashi, Junichi Nishimura, Taishi Hata, Tsunekazu Mizushima, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Masaki Mori

    ONCOLOGY LETTERS   Vol. 14 ( 4 ) page: 4483 - 4490   2017.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPANDIDOS PUBL LTD  

    The Golgi-associated PDZ- and coiled-coil motif-containing (GOPC) protein controls the intracellular trafficking of numerous integral membrane proteins. Knockdown of GOPC increases activation of the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 pathway and cancer cell progression in colorectal cancer. The present study aimed to clarify the correlation between GOPC expression and prognosis in colorectal cancer. Total RNA was extracted from 153 clinical colorectal cancer specimens and GOPC expression was evaluated using reverse transcription-quantitative polymerase chain reaction. The correlation between GOPC expression and clinicopathological factors was analyzed, along with the association of GOPC expression with overall survival (OS) and with recurrence-free survival (RFS). Lower expression of GOPC was significantly associated with a high frequency of venous invasion (P=0.001) and to poorer OS and RFS based on Kaplan-Meier analysis. In addition, multivariate analyses using a Cox proportional hazards model identified lower expression of GOPC to be an independent prognostic factor for colorectal cancer (hazard ratio=2.800; 95% confidence interval; 1.121-7.648; P=0.027). Lower expression of GOPC revealed a high frequency of venous invasion and associated with poorer prognosis for patients with colorectal cancer.

    DOI: 10.3892/ol.2017.6817

    Web of Science

    PubMed

  31. ポリアミンはLSD1を介して癌幹細胞のエピジェネティクスを制御する Reviewed

    玉利 慶介, 石井 秀始, 今野 雅允, 浅井 歩, 小関 準, 虎谷 昌保, 土岐 祐一郎, 森 正樹, 小川 和彦

    日本癌学会総会記事   Vol. 76回   page: P - 1207   2017.9

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  32. 膵癌のミトコンドリア代謝が関わるEMT現象の解明 Reviewed

    高岡 祐史, 石井 秀始, Colvin Hugh, 西田 尚弘, 今野 雅允, 浅井 歩, 川本 弘一, 小関 準, 玉利 慶介, 土岐 祐一郎, 森 正樹, 小川 和彦

    日本癌学会総会記事   Vol. 76回   page: P - 1181   2017.9

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  33. MicroRNA profiles involved in trifluridine resistance Reviewed

    Tsunekuni, K, Konno, M, Asai, A, Koseki, J, Kobunai, T, Takechi, T, Doki, Y, Mori, M, Ishii, H

    Oncotarget     page: .   2017.5

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  34. Clinical Significance of Histone Demethylase NO66 in Invasive Colorectal Cancer. Reviewed International journal

    Yujiro Nishizawa, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Ayumu Asai, Jun Koseki, Hidekazu Takahashi, Naotsugu Haraguchi, Junichi Nishimura, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Annals of surgical oncology   Vol. 24 ( 3 ) page: 841 - 849   2017.3

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    BACKGROUND: Targeting epigenetic regulators is a promising therapeutic strategy against cancer. However, because of the broad spectrum of targets, selective inhibition of cancer-associated genes remains a major challenge. To address this issue, we focused on the oncogene-regulated histone demethylase, nucleolar protein 66 (NO66 [C14orf169/MAPJD]), which is known to work coordinately with the well-characterized oncogene, c-MYC. METHODS: To investigate expression patterns and clinical significance of NO66 in colorectal cancer (CRC), we performed immunohistochemical staining in 114 CRC cases. We performed functional analysis of NO66 to evaluate its contribution to proliferation and migration ability in CRC cells in vitro. RESULTS: NO66 was selectively expressed in CRC tissues. Furthermore, high expression levels of NO66 were associated with cancer metastatic potential, including lymphatic duct invasion (p = 0.047), venous invasion (p = 0.033), and lymph node metastasis (p = 0.015). Multivariate analysis indicated that NO66 was an independent prognostic factor for overall survival. In vitro assays revealed that NO66 expression is closely associated with malignant potential, including proliferation, migration and anti-apoptotic activity. CONCLUSIONS: NO66 is an independent prognostic factor in CRC. The cancer-selective expression patterns and its involvement in metastatic phenotypes suggest that NO66 is not only a crucial biomarker but is also a promising therapeutic target in CRC.

    DOI: 10.1245/s10434-016-5395-9

    PubMed

  35. High expression of ADAMTS5 is a potent marker for lymphatic invasion and lymph node metastasis in colorectal cancer. Reviewed International journal

    Naotsugu Haraguchi, Nobuyoshi Ohara, Jun Koseki, Hidekazu Takahashi, Junichi Nishimura, Taishi Hata, Tsunekazu Mizushima, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Masaki Mori

    Molecular and clinical oncology   Vol. 6 ( 1 ) page: 130 - 134   2017.1

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    Members of the ADAMTS family contain propeptide, metalloproteinase and disintegrin domains and serve key roles for cancer cell proliferation, progression and metastasis. Although overexpression of ADAMTS5 has been reported in glioblastoma, and head and neck cancer, little has been demonstrated in colorectal cancer types. The present study aimed to clarify the significance of ADAMTS5 for clinicopathological factors and prognosis in colorectal cancer. The mRNA expression of ADAMTS5 was measured in 143 colorectal cancer specimens. ADAMTS5 expression was increased as the pathological stage increased. The expression of ADAMTS5 in stage III-IV colorectal cancer was significantly greater compared with that of stage 0-II colorectal cancer (P=0.0003). The median expression of ADAMTS5 was used to divide the ADAMTS5 higher expressing group and the ADAMTS5 lower expressing group to assess the correlation of ADAMTS5 expression with clinicopathological factors and prognosis. The proportions of lymphatic invasion and lymph node metastasis were significantly greater in the ADAMTS5 higher expressing group (P=0.0214 and P=0.0289 respectively). Overall survival and disease-free survival were assessed by the Kaplan-Meier curve with calculation of significance by the log-rank test; however, no significant difference was observed between the ADAMTS5 higher expressing group and the ADAMTS5 lower expressing group (P=0.7490 and P=0.9455, respectively). The present study confirmed high expression of ADAMTS5 as a potent marker for lymphatic invasion and lymphnode metastasis in colorectal cancer. To clarify the function of ADAMTS5 in colorectal cancer, further molecular investigations are required.

    DOI: 10.3892/mco.2016.1088

    PubMed

  36. The importance of mitochondrial folate enzymes in human colorectal cancer. Reviewed International journal

    Masaaki Miyo, Masamitsu Konno, Hugh Colvin, Naohiro Nishida, Jun Koseki, Koichi Kawamoto, Kenta Tsunekuni, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Oncology reports   Vol. 37 ( 1 ) page: 417 - 425   2017.1

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    Folate plays a pivotal role in the one-carbon metabolism needed for methylation reactions, nucleotide synthesis, and DNA repair. Although folate metabolism was recently shown to be associated with carcinogenesis in some solid tumors, the importance of folate metabolism in colorectal cancer remains unclear. In the present investigation we found that expression of three mitochondrial folate metabolic enzymes, serine hydroxymethyl transferase (SHMT2), methylenetetrahydrofolate dehydrogenase (MTHFD2) and aldehyde dehydrogenase 1 family member L2 (ALDH1L2), were upregulated in human colorectal tumor tissues compared to normal tissues. Colorectal cancer tissue samples were obtained from 117 consecutive patients. We evaluated the expression of the enzymes with immunohistochemical analysis and determined their relevance to clinicopathological characteristics and prognosis. Rates of recurrence-free survival (RFS) and overall survival (OS) in patients with high expression of SHMT2, MTHFD2 and ALDH1L2 tended to be lower than in patients with low expression of SHMT2, MTHFD2 and ALDH1L2 (P=0.446 and P=0.337, P=0.099 and P=0.064, P=0.178 and P=0.257, respectively). Notably, the combined high expression of SHMT2, MTHFD2 and ALDH1L2 (triple high) was more highly associated with poor prognosis than the individual expression levels (RFS; P=0.004 and OS; P=0.037). A multivariate analysis showed that triple high expression was independently associated with RFS (P=0.017). These findings suggested that mitochondrial folate metabolic enzymes could provide a potential therapeutic strategy for treating colorectal cancer.

    DOI: 10.3892/or.2016.5264

    PubMed

  37. 大腸がんにおけるヒストン脱メチル化酵素N066の臨床的意義の解明

    西沢佑次郎, 西田尚弘, 西田尚弘, 今野雅允, 今野雅允, 川本弘一, 小関準, 浅井歩, 浅井歩, 西村潤一, 畑泰司, 松田宙, 佐藤太郎, 水島恒和, 水島恒和, 山本浩文, 山本浩文, 土岐祐一郎, 森正樹, 石井秀始, 石井秀始

    日本がん転移学会学術集会・総会プログラム抄録集   Vol. 26th   page: 105   2017

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    J-GLOBAL

  38. Metabolic Adaptation to Nutritional Stress in Human Colorectal Cancer. Reviewed International journal

    Masaaki Miyo, Masamitsu Konno, Naohiro Nishida, Toshinori Sueda, Kozo Noguchi, Hidetoshi Matsui, Hugh Colvin, Koichi Kawamoto, Jun Koseki, Naotsugu Haraguchi, Junichi Nishimura, Taishi Hata, Noriko Gotoh, Fumio Matsuda, Taroh Satoh, Tsunekazu Mizushima, Hiroshi Shimizu, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Scientific reports   Vol. 6   page: 38415 - 38415   2016.12

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    Tumor cells respond to their microenvironment, which can include hypoxia and malnutrition, and adapt their metabolism to survive and grow. Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters. However, the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear. We found that colorectal cancer cells survived under the condition of glucose depletion, and their resistance to such conditions depended on genomic alterations rather than on KRAS mutation alone. Metabolomic analysis demonstrated that those cells maintained tricarboxylic acid cycle activity and ATP production under such conditions. Furthermore, we identified pivotal roles of GLUD1 and SLC25A13 in nutritional stress. GLUD1 and SLC25A13 were associated with tumor aggressiveness and poorer prognosis of colorectal cancer. In conclusion, GLUD1 and SLC25A13 may serve as new targets in treating refractory colorectal cancer which survive in malnutritional microenvironments.

    DOI: 10.1038/srep38415

    PubMed

  39. Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer. Reviewed International journal

    Hugh Colvin, Naohiro Nishida, Masamitsu Konno, Naotsugu Haraguchi, Hidekazu Takahashi, Junichi Nishimura, Taishi Hata, Koichi Kawamoto, Ayumu Asai, Kenta Tsunekuni, Jun Koseki, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Scientific reports   Vol. 6   page: 36289 - 36289   2016.11

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    Deranged metabolism is a hallmark of cancer, playing a significant role in driving the disease process. One such example is the induction of carcinogenesis by the oncometabolite D-2 hydroxyglutarate (D-2HG), which is produced by the mutated enzyme isocitrate dehydrogenase (IDH) occurring in subsets of leukaemias and brain tumours. The oncogenic property of D-2HG appears to stem from its ability to interfere with the activities of α-ketoglutarate-dependent dioxygenases, including the Jumonji family histone demethylases. Here, we find in colorectal cancer cells that even in the absence of IDH mutation, the levels of D-2HG and its enantiomer L-2HG were elevated through glutamine anaplerosis. D-2HG, but not L-2HG, increased the trimethylation of histone H3 lysine 4 of the promoter region of ZEB1, a master regulator of epithelial-mesenchymal transition (EMT), and increased the expression of the ZEB1 gene to directly induce EMT in colorectal cancer cells. EMT promotes the ability of cancer cells to invade the local tissue and enter into the bloodstream, leading to distant organ metastasis. D-2HG levels were elevated in colorectal cancer specimens, particularly in those associated with distant metastasis, supporting the observations in vitro and implicating the contribution of D-2HG in metastasis, the major cause of death in this disease.

    DOI: 10.1038/srep36289

    PubMed

  40. MicroRNA miR-374, a potential radiosensitizer for carbon ion beam radiotherapy. Reviewed International journal

    Sung-Jae Baek, Katsutoshi Sato, Naohiro Nishida, Jun Koseki, Rikako Azuma, Koichi Kawamoto, Masamitsu Konno, Kazuhiko Hayashi, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii, Kazuhiko Ogawa

    Oncology reports   Vol. 36 ( 5 ) page: 2946 - 2950   2016.11

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    In this study, we compared the microRNA (miRNA) profiles of a control and X-ray- and carbon ion beam-resistant cells to identify miRNAs that can be used as radiosensitizers and biomarkers. Mouse squamous cell carcinoma line NR-S1, its X-ray-resistant derivative X60, and its carbon ion beam‑resistant derivative C30 were subjected to miRNA microarray analysis. Expression of miRNAs shown to be upregulated or downregulated in the microarray analysis was confirmed by qRT-PCR. Downregulated miRNAs were overexpressed in human pancreatic cancer cell lines PANC1 and MIA PaCa-2, and the resulting cells were tested for radiosensitivity using colony-forming and sphere-forming assays. Of 1,265 miRNAs analyzed, 4 were downregulated and 11 were upregulated in X-ray-resistant and carbon ion beam-resistant cells. Two of the downregulated miRNAs, miR-196 and miR-374, were selected for overexpression in PANC1 and MIA PaCa-2 cells. Overexpression of miR-374 sensitized PANC-1 and MIA PaCa-2 cells toward carbon ion beam radiation. miRNA miR-374 has the potential to be a new radiosensitizer for carbon ion beam radiotherapy and a new biomarker to determine the optimal treatment for cancer.

    DOI: 10.3892/or.2016.5122

    PubMed

  41. Molecular Orbital Study of the Formation of Intramolecular Hydrogen Bonding of a Ligand Molecule in a Protein Aromatic Hydrophobic Pocket Reviewed

    Jun Koseki, Hiroaki Gouda, Shuichi Hirono

    CHEMICAL & PHARMACEUTICAL BULLETIN   Vol. 64 ( 7 ) page: 1031 - 1035   2016.7

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:PHARMACEUTICAL SOC JAPAN  

    The natural product argadin is a cyclopentapeptide chitinase inhibitor that binds to chitinase B (ChiB) from the pathogenic bacteria Serratia inarcescens. N-w-Acetyl-L-arginine and L-aminoadipic acid of argadin form intramolecular ionic hydrogen bonds in the aromatic hydrophobic pocket of ChiB. We performed ab initio molecular orbital and density functional theory calculations to elucidate the role of this intramolecular hydrogen bonding on intermolecular interactions between argadin and ChiB. We found that argadin accrues large stabilization energies from the van der Waals dispersion interactions, such as CH-pi, pi-pi, and pi-lone pair interactions, in the aromatic hydrophobic pocket of ChiB, although intramolecular hydrogen bonding within argadin might result in loss of entropy. The intramolecular ionic hydrogen bonding formation canceled local molecular charges and provided good van der Waals interactions with surrounding aromatic residues.

    DOI: 10.1248/cpb.c16-00126

    Web of Science

  42. A Trans-omics Mathematical Analysis Reveals Novel Functions of the Ornithine Metabolic Pathway in Cancer Stem Cells. Reviewed International journal

    Jun Koseki, Hidetoshi Matsui, Masamitsu Konno, Naohiro Nishida, Koichi Kawamoto, Yoshihiro Kano, Masaki Mori, Yuichiro Doki, Hideshi Ishii

    Scientific reports   Vol. 6   page: 20726 - 20726   2016.2

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    Bioinformatics and computational modelling are expected to offer innovative approaches in human medical science. In the present study, we performed computational analyses and made predictions using transcriptome and metabolome datasets obtained from fluorescence-based visualisations of chemotherapy-resistant cancer stem cells (CSCs) in the human oesophagus. This approach revealed an uncharacterized role for the ornithine metabolic pathway in the survival of chemotherapy-resistant CSCs. The present study fastens this rationale for further characterisation that may lead to the discovery of innovative drugs against robust CSCs.

    DOI: 10.1038/srep20726

    PubMed

  43. BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells. Reviewed International journal

    Toshinori Sueda, Daisuke Sakai, Koichi Kawamoto, Masamitsu Konno, Naohiro Nishida, Jun Koseki, Hugh Colvin, Hidekazu Takahashi, Naotsugu Haraguchi, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Scientific reports   Vol. 6   page: 18949 - 18949   2016.1

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    Although BRAF(V600E) mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAF(V600E) inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAF(V600E) inhibition activates AMP-activated protein kinase (AMPK), which induces autophagy as a mechanism of therapeutic resistance in human cancers. The present data show AMPK-dependent cytoprotective roles of autophagy under conditions of therapeutic BRAF(V600E) inhibition, and AMPK was negatively correlated with BRAF(V600E)-dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAF(V600E) inhibition and concomitant suppression of autophagy led to the induction of apoptosis. Taken together, present experiments indicate that AMPK plays a role in the survival of BRAF(V600E) CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF(V600E) CRC cells.

    DOI: 10.1038/srep18949

    PubMed

  44. Classification and Contribution Analysis of Aromatic Clusters in Protein-Ligand Complexes Reviewed

    Hiroyuki Yamasaki, Jun Koseki, Yoshihiko Nishibata, Shuichi Hirono

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   Vol. 136 ( 1 ) page: 97 - 99   2016.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:PHARMACEUTICAL SOC JAPAN  

    Intermolecular interactions are key features in the stabilization or destabilization of complexes. In particular, interactions involving aromatic rings have been extensively studied both theoretically and experimentally. Studies have shown that aromatic-aromatic interactions can be categorized by ring-ring orientation into a variety of different types, such as stacking interactions and T-shaped interactions. Because these different orientations affect stabilization, analyses of such interactions, for example ab initio molecular orbital calculations, are applied to pairs of aromatic rings, both in model systems and real systems. An important series of aromatic-aromatic interactions include those between pairs of aromatic residues in proteins. These residues have been studied computationally using both a theoretical chemistry approach and a knowledge-based analys. Protein 3D structural information is essential for knowledge-based studies of aromatic-aromatic interactions in protein-ligand complexes. Some databases filter entries from the Protein Data Bank (PDB) using criteria that make them suitable for computational approaches involving specific research targets. Lanzarotti et al. have shown that aromatic clusters in which three or more aromatic residues are in close proximity to each other are found in many protein structures, expanding pairwise aromatic-aromatic interactions. Moreover, these clusters are thought to be important in terms of protein function, structural stability and ligand recognition. Here, we show that aromatic clusters, as well as individual proteins, are found in a variety of protein-ligand complexes. As such, we anticipate that these clusters might have a significant role in ligand binding and could help in efficient ligand design.

    DOI: 10.1248/yakushi.15-00230-1

    Web of Science

  45. A crucial epithelial to mesenchymal transition regulator, Sox4/Ezh2 axis is closely related to the clinical outcome in pancreatic cancer patients. Reviewed International journal

    Shinichiro Hasegawa, Hiroaki Nagano, Masamitsu Konno, Hidetoshi Eguchi, Akira Tomokuni, Yoshito Tomimaru, Tadafumi Asaoka, Hiroshi Wada, Naoki Hama, Koichi Kawamoto, Shigeru Marubashi, Naohiro Nishida, Jun Koseki, Masaki Mori, Yuichiro Doki, Hideshi Ishii

    International journal of oncology   Vol. 48 ( 1 ) page: 145 - 52   2016.1

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    Pancreatic cancer has a poor prognosis because of its high invasiveness and recurrence, and these properties closely link to the phenomenon of epithelial-mesenchymal transition (EMT). Recently, it has been reported that Sox4 is indispensable for EMT in vitro and in vivo and regulates various master regulators of EMT including Zeb, Twist and Snail. Moreover, Sox4 induces the transcription of Ezh2 which is the histone methyltransferase, and reprograms the cancer epigenome to promote EMT and metastasis. Therefore, the present study evaluated the importance of Sox4, Ezh2 and miR-335, which regulate Sox4 expression epigenetically, in clinical samples with pancreatic cancer. This retrospective analysis included data from 36 consecutive patients who underwent complete surgical resection for pancreatic cancer and did not undergo any preoperative therapies. We assessed the clinical significance of Sox4/Ezh2 axis and miR-335 expression, using immunohistochemistry and qRT-PCR with laser captured microdissection (LCM). The Sox4 positive patients had significantly worse prognosis as for disease-free survival (DFS) (P=0.0154) and the Ezh2-positive patients had significantly worse prognosis as for overall survival (OS) (P=0.0347). The miR-335 expression was inversely correlated with Sox4 expression in the identical clinical specimens, but it was not related to the prognosis. Sox4/Ezh2 axis was closely associated with the prognosis in pancreatic cancer patients.

    DOI: 10.3892/ijo.2015.3258

    PubMed

  46. c-Met affects gemcitabine resistance over carcinogenesis in a mouse model of pancreatic cancer Reviewed

    Noguchi, K, Konno, M, Eguchi, H, Kawamoto, K, Mukai, R, Nishida, N, Koseki, J, Wada, H, Akita, H, Satoh, T, Marubashi, S, Nagano, H, Doki, Y, Mori, M, Ishii, H

    Oncology Letters     page: .   2016

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  47. Fetal hepatocyte derived culture medium elicits adipocyte differentiation to bile duct cell lineages in mouse Reviewed

    Ogawa, H, Konno, M, Kawamoto, K, Nishida, N, Koseki, J, Mizushima, T, Satoh, T, Eguchi, H, Doki, Y, Mori, M, Ishii, H

    Biomedical Reports     page: .   2016

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  48. Prognostic Impact of Peritumoral IL-17-Positive Cells and IL-17 Axis in Patients with Intrahepatic Cholangiocarcinoma. Reviewed International journal

    Kei Asukai, Koichi Kawamoto, Hidetoshi Eguchi, Masamitsu Konno, Naohiro Nishida, Jun Koseki, Kozo Noguchi, Shinichiro Hasegawa, Hisataka Ogawa, Daisaku Yamada, Yoshito Tomimaru, Akira Tomokuni, Tadafumi Asaoka, Takehiro Noda, Hiroshi Wada, Kunihito Gotoh, Shigeru Marubashi, Hiroaki Nagano, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Annals of surgical oncology   Vol. 22 Suppl 3   page: S1524-31 - 1531   2015.12

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    BACKGROUND: Development of cancer has been linked to inflammatory cytokines such as interleukin (IL)-6 and IL-17. In this study, we assessed the expression of these cytokines in intrahepatic cholangiocarcinoma (ICC) and determined their correlation to the survival probability. METHODS: A total of 72 consecutive patients who underwent curative resection of ICC at Osaka University Hospital from March 1998 to November 2014 were enrolled. Immunohistochemical analysis was performed for IL-17 and its receptor A (IL-17RA), as well as IL-6. Enzyme-linked immunosorbent assay (ELISA) was performed for preoperative plasma levels of IL-6 and IL-17 in 32 patients with ICC. RESULTS: Immunohistochemical analysis showed that the IL-6(high) (n = 34) and IL-17RA(high) (n = 29) groups had significantly worse disease-free survival (DFS) than IL-6(low) (n = 38) and IL-17RA(low) (n = 43) groups, respectively. Although IL-17(+) cells were abundant in the intratumoral area, patients with high peritumoral, but not intratumoral, IL-17(+) cells (n = 28) corresponded with a significantly lower overall survival (OS) and DFS (OS, p = 0.023; DFS, p = 0.026) than those with low group. Moreover, multivariate Cox proportional hazards analysis revealed that IL-6, peritumoral IL-17(+), and IL-17RA are independent prognostic factors for DFS (p = 0.023, p = 0.0088, p = 0.039, respectively). In addition, high preoperative plasma levels of IL-6 in patients with ICC corresponded with significantly lower DFS (p = 0.002). CONCLUSIONS: Our data suggested that IL-6, peritumoral IL-17(+) cells, and IL-17RA expression are postoperative useful markers for predicting recurrence in patients with ICC.

    DOI: 10.1245/s10434-015-4782-y

    PubMed

  49. Cancer stem cells: The potential of carbon ion beam radiation and new radiosensitizers (Review). Reviewed International journal

    Sung-Jae Baek, Hideshi Ishii, Keisuke Tamari, Kazuhiko Hayashi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Jun Koseki, Takahito Fukusumi, Shinichiro Hasegawa, Hisataka Ogawa, Atsushi Hamabe, Masaaki Miyo, Kozo Noguchi, Yuji Seo, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa

    Oncology reports   Vol. 34 ( 5 ) page: 2233 - 7   2015.11

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    Cancer stem cells (CSCs) are a small population of cells in cancer with stem-like properties such as cell proliferation, multiple differentiation and tumor initiation capacities. CSCs are therapy-resistant and cause cancer metastasis and recurrence. One key issue in cancer therapy is how to target and eliminate CSCs, in order to cure cancer completely without relapse and metastasis. To target CSCs, many cell surface markers, DNAs and microRNAs are considered as CSC markers. To date, the majority of the reported markers are not very specific to CSCs and are also present in non-CSCs. However, the combination of several markers is quite valuable for identifying and targeting CSCs, although more specific identification methods are needed. While CSCs are considered as critical therapeutic targets, useful treatment methods remain to be established. Epigenetic gene regulators, microRNAs, are associated with tumor initiation and progression. MicroRNAs have been recently considered as promising therapeutic targets, which can alter the therapeutic resistance of CSCs through epigenetic modification. Moreover, carbon ion beam radiotherapy is a promising treatment for CSCs. Evidence indicates that the carbon ion beam is more effective against CSCs than the conventional X-ray beam. Combination therapies of radiosensitizing microRNAs and carbon ion beam radiotherapy may be a promising cancer strategy. This review focuses on the identification and treatment resistance of CSCs and the potential of microRNAs as new radiosensitizers and carbon ion beam radiotherapy as a promising therapeutic strategy against CSCs.

    DOI: 10.3892/or.2015.4236

    PubMed

  50. Cyclin G2: A novel independent prognostic marker in pancreatic cancer. Reviewed International journal

    Shinichiro Hasegawa, Hiroaki Nagano, Masamitsu Konno, Hidetoshi Eguchi, Akira Tomokuni, Yoshito Tomimaru, Hiroshi Wada, Naoki Hama, Koichi Kawamoto, Shogo Kobayashi, Shigeru Marubashi, Naohiro Nishida, Jun Koseki, Noriko Gotoh, Shouichi Ohno, Norikazu Yabuta, Hiroshi Nojima, Masaki Mori, Yuichiro Doki, Hideshi Ishii

    Oncology letters   Vol. 10 ( 5 ) page: 2986 - 2990   2015.11

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    Unlike other cyclins that positively regulate the cell cycle, cyclin G2 (CCNG2) regulates cell proliferation as a tumor suppressor gene. A decreased CCNG2 expression serves as a marker for poor prognosis in several types of cancer. The aim of the present study was to clarify the correlation of CCNG2 expression with overall survival and histopathological factors in pancreatic cancer patients. This retrospective analysis included data from 36 consecutive patients who underwent complete surgical resection for pancreatic cancer and did not undergo any preoperative therapies. The association between prognoses and the expression of CCNG2 was assessed using immunohistochemical staining. Multivariate analysis identified that the expression of CCNG2 is an independent prognostic factor. In addition, the Kaplan-Meier curve for overall survival revealed that decreased expression of CCNG2 was a consistent indicator of poor prognosis in pancreatic cancer patients (P=0.0198). A decreased CCNG2 expression significantly correlated with venous invasion in tumor specimens and the tumor invasion depth. In conclusion, CCNG2 expression inversely reflected cancer progression and may be a novel, independent prognostic marker in pancreatic cancer.

    DOI: 10.3892/ol.2015.3667

    PubMed

  51. ハイスループットスクリーニングを用いた子宮頸癌癌幹細胞を標的とした放射線増感剤の同定 Reviewed

    玉利 慶介, 石井 秀始, 今野 雅允, 西田 尚弘, 川本 弘一, 小関 準, 白 成栽, 土岐 祐一郎, 森 正樹, 小川 和彦

    日本癌学会総会記事   Vol. 74回   page: P - 2342   2015.10

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  52. [Therapeutic Implication Targeting for Cancer Stem Cells]. Reviewed

    Kozo Noguchi, Masamitsu Konno, Naohiro Nishida, Koichi Kawamoto, Jun Koseki, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori, Taro Satoh, Hideshi Ishii

    Gan to kagaku ryoho. Cancer & chemotherapy   Vol. 42 ( 9 ) page: 1036 - 9   2015.9

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    Cancer has been viewed as a heterogeneous population of cells.While the large majority of cells that constituting tumors are differentiated, and eventually stop dividing, only a minority population of cells, termed cancer stem cells, is capable of unlimited self-renewal and multi-differentiation, just like somatic stem cells in normal tissues.Cancer stem cells have been identified in a variety of cancers of the blood, brain, stomach, colon, and pancreas.In this review we present current evidence supporting the cancer stem cell model of tumor progression, and discuss the experimental and therapeutic implications.

    PubMed

  53. Susceptibility of pancreatic cancer stem cells to reprogramming. Reviewed International journal

    Kozo Noguchi, Hidetoshi Eguchi, Masamitsu Konno, Koichi Kawamoto, Naohiro Nishida, Jun Koseki, Hiroshi Wada, Shigeru Marubashi, Hiroaki Nagano, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Cancer science   Vol. 106 ( 9 ) page: 1182 - 7   2015.9

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    Previous reports have indicated that reprogramming technologies may be useful for altering the malignant phenotype of cancer cells. Although somatic stem cells in normal tissues are more sensitive to reprogramming induction than differentiated cells, it remains to be elucidated whether any specific subpopulations are sensitive to reprogramming in heterogeneous tumor tissues. Here we examined the susceptibility of pancreatic cancer stem cells (CSC) and non-CSC to reprogramming. To characterize CSC populations, we focused on c-Met signaling, which has been identified as a marker of CSC in mouse experiments in vivo. Cells that expressed high levels of c-Met showed higher CSC properties, such as tumor-initiating capacity, and resistance to gemcitabine. Real-time reverse transcription-polymerase chain reaction in cells expressing high levels of c-Met revealed endogenous expression of reprogramming factors, such as OCT3/4, SOX2, KLF4 and cMYC. Introduction of these four factors resulted in higher alkaline phosphatase staining in cells with high c-Met expression than in controls. Therefore, the study results demonstrate that cellular reprogramming may be useful for extensive epigenetic modification of malignant features of pancreatic CSC.

    DOI: 10.1111/cas.12734

    PubMed

  54. Tumour-suppressive function of SIRT4 in human colorectal cancer Reviewed

    M. Miyo, H. Yamamoto, M. Konno, H. Colvin, N. Nishida, J. Koseki, K. Kawamoto, H. Ogawa, A. Hamabe, M. Uemura, J. Nishimura, T. Hata, I. Takemasa, T. Mizushima, Y. Doki, M. Mori, H. Ishii

    BRITISH JOURNAL OF CANCER   Vol. 113 ( 3 ) page: 492 - 499   2015.7

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    Background: SIRT4, which is localised in the mitochondria, is one of the least characterised members of the sirtuin family of nicotinamide adenine dinucleotide-dependent enzymes that play key roles in multiple cellular processes such as metabolism, stress response and longevity. There are only a few studies that have characterised its function and assessed its clinical significance in human cancers.
    Methods: We established colorectal cancer cell lines (SW480, HCT116, and HT29) overexpressing SIRT4 and investigated their effects on proliferation, migration and invasion, as well as E-cadherin expression, that negatively regulates tumour invasion and metastases. The associations between SIRT4 expression in colorectal cancer specimens and clinicopathological features including prognosis were assessed by immunohistochemistry.
    Results: SIRT4 upregulated E-cadherin expression and suppressed proliferation, migration and invasion through inhibition of glutamine metabolism in colorectal cancer cells. Moreover, SIRT4 expression in colorectal cancer decreased with the progression of invasion and metastasis, and a low expression level of SIRT4 was correlated with a worse prognosis.
    Conclusions: SIRT4 has a tumour-suppressive function and may serve as a novel therapeutic target in colorectal cancer.

    DOI: 10.1038/bjc.2015.226

    Web of Science

  55. Pyruvate kinase M2, but not M1, allele maintains immature metabolic states of murine embryonic stem cells. Reviewed International journal

    Masamitsu Konno, Hideshi Ishii, Jun Koseki, Nobuhiro Tanuma, Naohiro Nishida, Koichi Kawamoto, Tatsunori Nishimura, Asuka Nakata, Hidetoshi Matsui, Kozou Noguchi, Miyuki Ozaki, Yuko Noguchi, Hiroshi Shima, Noriko Gotoh, Hiroaki Nagano, Yuichiro Doki, Masaki Mori

    Regenerative therapy   Vol. 1   page: 63 - 71   2015.6

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    The M2 isoform of pyruvate kinase, the final rate-limiting enzyme of aerobic glycolysis, is expressed during embryonic development. In contrast, the M1 isoform is expressed in differentiated cells due to alternative splicing. Here we investigated murine embryonic stem cells (ESCs) with Pkm1 or Pkm2 knock-in alleles. Pkm1 allele knock-in resulted in excessive oxidative phosphorylation and induced the formation of cysteine-thiol disulfide-dependent complexes of forkhead box class-O (FOXO) transcription factors, which resulted in altered endoderm differentiation. In contrast, Pkm2 knock-in induced synthesis of a methylation-donor, S-adenosylmethionine, and increased unsaturated eicosanoid groups, which contributed to the redox control and maintenance of ESC undifferentiated status. Because PKM2 is also a critical enzyme for the cancer-specific Warburg effect, our results demonstrate an important role for the Pkm2 allele in establishing intracellular redox conditions and modulating PKM1-dependent oxidative phosphorylation events to achieve an appropriate ESC differentiation program.

    DOI: 10.1016/j.reth.2015.01.001

    PubMed

  56. Design and Synthesis of Labystegines, Hybrid Iminosugars from LAB and Calystegine, as Inhibitors of Intestinal alpha-Glucosidases: Binding Conformation and Interaction for ntSI Reviewed

    Atsushi Kato, Zhao-Lan Zhang, Hong-Yao Wang, Yue-Mei Jia, Chu-Yi Yu, Kyoko Kinami, Yuki Hirokami, Yutaro Tsuji, Isao Adachi, Robert J. Nash, George W. J. Fleet, Jun Koseki, Izumi Nakagome, Shuichi Hirono

    JOURNAL OF ORGANIC CHEMISTRY   Vol. 80 ( 9 ) page: 4501 - 4515   2015.5

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    This paper identifies the required configuration and orientation of alpha-glucosidase inhibitors, miglitol, alpha-1-C-butyl-DNJ, and alpha-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH-pi interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3(S)-hydroxy labystegine (6a) inherited the selectivity against intestinal alpha-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia.

    DOI: 10.1021/acs.joc.5b00342

    Web of Science

  57. The combination of the expression of hexokinase 2 and pyruvate kinase M2 is a prognostic marker in patients with pancreatic cancer. Reviewed International journal

    Hisataka Ogawa, Hiroaki Nagano, Masamitsu Konno, Hidetoshi Eguchi, Jun Koseki, Koichi Kawamoto, Naohiro Nishida, Hugh Colvin, Akira Tomokuni, Yoshito Tomimaru, Naoki Hama, Hiroshi Wada, Shigeru Marubashi, Shogo Kobayashi, Masaki Mori, Yuichiro Doki, Hideshi Ishii

    Molecular and clinical oncology   Vol. 3 ( 3 ) page: 563 - 571   2015.5

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    Metabolism may determine the biologically malignant behavior of pancreatic cancer. To investigate the significance and prognostic value of cancer metabolism in cancer patients, we investigated the expression of two key enzymes in anaerobic glycolysis, hexokinase 2 (HK2) and pyruvate kinase isoenzyme type M2 (PKM2), in surgical specimens obtained from 36 patients who underwent curative resection of pancreatic ductal carcinoma. The hk2-glycolysis axis is a key system in the clinical imaging of tumors via positron emission tomography. Immunohistochemical staining for hk2 and pkm2 was performed and the data were statistically analyzed to evaluate their prognostic power. The expression of hk2 and pkm2 was associated with clinicopathological variables and patient prognosis, including overall survival, local recurrence-free survival and distant metastasis-free survival. Staining for hk2 was negative and positive in 42 and 58% of the patients, respectively, whereas staining for pkm2 was negative and positive in 56 and 44%, respectively; hk2-positive staining was correlated with progressive pathological tumor stage (pT3 vs. pT1 and pT2; P=0.017). In the univariate analysis, the positive expression of hk2 and pkm2, pathological stage (pT3 vs. pT1 and pT2) and nodal metastasis were significantly correlated with poor prognosis (P<0.03). In the multivariate analysis, pathological nodal metastasis was an independent prognostic factor for overall survival, whereas the positive expression of hk2 and pkm2 exhibited borderline significance (P=0.08 and 0.12, hazard ratio = 2.57 and 2.16, respectively). In addition, the combination of high expression of hk2 as well as pkm2 was found to be significant (P<0.05). These results suggested that the expression of hk2 and pkm2, particularly their combination, in surgical specimens obtained during curative resection, may predict an unfavorable clinical outcome in patients with pancreatic cancer.

    PubMed

  58. Novel markers of cancer stem cells in head and neck squamous cell carcinoma Reviewed

    T. Fukusumi, H. Ishii, J. Koseki, A. Hanamoto, S. Nakahara, Y. Yamamoto, H. Inohara

    Cancer Cell & Microenvironment   Vol. 2   page: e701-1 - e701-1   2015.4

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  59. Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer. Reviewed International journal

    Jun Koseki, Hugh Colvin, Takahito Fukusumi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Hidetoshi Matsui, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    International journal of oncology   Vol. 46 ( 3 ) page: 1181 - 91   2015.3

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Bioinformatics and computational modeling offer innovative approaches to investigate cancer metabolism and predict the secondary and tertiary cellular responses. Dysregulation of metabolism has also been implicated in the pathophysiology of cancer. A significant proportion of patients with glioblastoma and hematological malignancies harbor the mutated forms of the oxidative phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that D2HG can also be produced in the absence of mutated IDH, through an alternative route involving over-activated MYC signaling. We developed a novel methodology to computationally analyze gene expression in colorectal cancer (CRC), and identified novel sets of genes that are associated with patient survival. The study of OxPhos-related genes revealed that an imbalance between the expression of IDH1 and IDH2, defined as overexpression of one isoform in relation to the other, was associated with worse prognosis in CRC patients. This effect was further accentuated by reduced expression of the β-oxygenation enzyme, 3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute to metabolism of intracellular D2HG. The present computational analysis revealed a novel and potential mechanism of CRC development, through over-production of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the β-oxidization pathway is diminished. Additional validation analysis with another gene expression dataset resulted in IDH1/2 imbalanced expression with a shorter DFS compared with balanced expression. Altogether, these findings provide a strong rationale for studying this mechanism further in order to discover novel therapeutic targets for the treatment of CRC.

    DOI: 10.3892/ijo.2015.2833

    PubMed

  60. Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming. Reviewed International journal

    Masamitsu Konno, Jun Koseki, Koichi Kawamoto, Naohiro Nishida, Hidetoshi Matsui, Dyah Laksmi Dewi, Miyuki Ozaki, Yuko Noguchi, Koshi Mimori, Noriko Gotoh, Nobuhiro Tanuma, Hiroshi Shima, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    PloS one   Vol. 10 ( 7 ) page: e0132789   2015

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    Noncoding microRNAs inhibit translation and lower the transcript stability of coding mRNA, however miR-369 s, in aberrant silencing genomic regions, stabilizes target proteins under cellular stress. We found that in vitro differentiation of embryonic stem cells led to chromatin methylation of histone H3K4 at the miR-369 region on chromosome 12qF in mice, which is expressed in embryonic cells and is critical for pluripotency. Proteomic analyses revealed that miR-369 stabilized translation of pyruvate kinase (Pkm2) splicing factors such as HNRNPA2B1. Overexpression of miR-369 stimulated Pkm2 splicing and enhanced induction of cellular reprogramming by induced pluripotent stem cell factors, whereas miR-369 knockdown resulted in suppression. Furthermore, immunoprecipitation analysis showed that the Argonaute complex contained the fragile X mental retardation-related protein 1 and HNRNPA2B1 in a miR-369-depedent manner. Our findings demonstrate a unique role of the embryonic miR-369-HNRNPA2B1 axis in controlling metabolic enzyme function, and suggest a novel pathway linking epigenetic, transcriptional, and metabolic control in cell reprogramming.

    DOI: 10.1371/journal.pone.0132789

    PubMed

  61. MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells. Reviewed International journal

    Hisataka Ogawa, Xin Wu, Koichi Kawamoto, Naohiro Nishida, Masamitsu Konno, Jun Koseki, Hidetoshi Matsui, Kozou Noguchi, Noriko Gotoh, Tsuyoshi Yamamoto, Kanjiro Miyata, Nobuhiro Nishiyama, Hiroaki Nagano, Hirofumi Yamamoto, Satoshi Obika, Kazunori Kataoka, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    PloS one   Vol. 10 ( 5 ) page: e0127119   2015

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    Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR) 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

    DOI: 10.1371/journal.pone.0127119

    PubMed

  62. Visualization and characterization of cancer stem-like cells in cervical cancer. Reviewed International journal

    Kazuhiko Hayashi, Keisuke Tamari, Hideshi Ishii, Masamitsu Konno, Naohiro Nishida, Koichi Kawamoto, Jun Koseki, Takahito Fukusumi, Yoshihiro Kano, Shimpei Nishikawa, Masaaki Miyo, Kozo Noguchi, Hisataka Ogawa, Atsushi Hamabe, Yuji Seo, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa

    International journal of oncology   Vol. 45 ( 6 ) page: 2468 - 74   2014.12

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    Cancer stem cells (CSCs), defined by their differentiation capacity, self-renewal capacity, and maintenance of proliferation, have been identified in many tumors, including cervical cancer. Current studies identify CSCs by several specific biomarkers; however, it is difficult to monitor cervical CSCs in real-time in vitro and in vivo. Recent research reported the visualization of CSCs in breast cancer and gliomas using green fluorescent protein, ZsGreen, fused to a degron motif ornithine decarboxylase (ODC), which is destroyed by proteasomes. Accordingly, CSCs have low 26S proteasome activity, whereas non-CSCs have high 26S proteasome activity. Therefore, it is possible to observe CSCs by their accumulation of the fluorescent ZsGreen protein. In this study, we investigated optical imaging parameters to evaluate CSCs using two human cervical cancer cell lines: CaSki and HeLa. We defined populations as cell types having high- and low ZsGreen-cODC (high- and low-Zs, respectively) expression levels. The results of a sphere-forming assay revealed that the self-renewal ability of the high-Zs population was significantly higher than that of the low-Zs population. A tumorigenicity assay confirmed that the high-Zs population exhibited higher tumorigenic potential than the low-Zs population. The radioresistance of the high-Zs population of both HeLa and CaSki cells and the chemoresistance of the high-Zs population of CaSki cells were confirmed by a clonogenic survival assay and the tetrazolium dye assay, respectively. These results indicate that high-Zs populations of both the HeLa and CaSki cell lines possess CSC-like properties and therapeutic resistance. In conclusion, we successfully visualized CSC-like cells using a fluorescent protein system.

    DOI: 10.3892/ijo.2014.2670

    PubMed

  63. Identification of chemoradiation-resistant osteosarcoma stem cells using an imaging system for proteasome activity. Reviewed International journal

    Keisuke Tamari, Kazuhiko Hayashi, Hideshi Ishii, Yoshihiro Kano, Masamitsu Konno, Koichi Kawamoto, Naohiro Nishida, Jun Koseki, Takahito Fukusumi, Shinichiro Hasegawa, Hisataka Ogawa, Atsushi Hamabe, Masaaki Miyo, Kozo Noguchi, Yuji Seo, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa

    International journal of oncology   Vol. 45 ( 6 ) page: 2349 - 54   2014.12

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    Osteosarcoma is the most common primary bone malignancy in pediatric and adolescent populations. Recurrence and metastatic potential can be due to a subpopulation of cells with stem cell-like characteristics, such as tumor-initiating cells (TICs), which maintain the capacity to regenerate entire tumors. Targeting the TICs in osteosarcoma is a promising avenue for the development of new therapies for this devastating disease. TICs are usually quiescent with a low protein turnover, decreased metabolism, and downregulation of proteasome activity. Recently, cancer cells with low proteasome activity have been identified as TICs in several types of cancer. We stably infected two osteosarcoma cell lines, MG-63 and U2-OS, with an expression vector for a fusion protein between the green fluorescent protein, ZsGreen, and the C-terminal degron of the murine ornithine decarboxylase to monitor the 26S proteasome activity in living cells. We separated the osteosarcoma cells with low proteasome activity using fluorescence-activated cell sorting (FACS) and verified whether these ZsGreen+ cells had TIC-like properties. The ZsGreen+ cells showed enhanced sphere formation capacity and underwent asymmetric divisions into ZsGreen+ and ZsGreen- cells, whereas ZsGreen- cells underwent only symmetric divisions into ZsGreen- cells. Moreover, the ZsGreen+ cells were more chemo- and radioresistant. Thus, the present study demonstrated that chemoradiation-resistant TICs can be visualized by this system and suggested the rationale for further study of osteosarcoma stem cells.

    DOI: 10.3892/ijo.2014.2671

    PubMed

  64. Cancer stem cells of the digestive system. Reviewed International journal

    Hugh S Colvin, Naohiro Nishida, Jun Koseki, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Japanese journal of clinical oncology   Vol. 44 ( 12 ) page: 1141 - 9   2014.12

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    Stem cells of the digestive system are ideal in many ways for research, given they are abundant, highly proliferative and have a uniform structural arrangement. This in turn has enormously aided the research of cancer stem cells of the digestive system, which is now shaping our understanding of cancer stem cells. In this review, the recent advances in the understanding of cancer stem cells of the digestive system have been summarized, including aspects such as their identification, origin, cell-cycle dormancy, relationship with epithelial-mesenchymal transition, cellular metabolism and the underlying molecular mechanisms. Newly acquired knowledge concerning cancer stem cells have led to the development of novel cancer therapeutics with provisional yet encouraging results.

    DOI: 10.1093/jjco/hyu146

    PubMed

  65. Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. Reviewed International journal

    Atsushi Hamabe, Masamitsu Konno, Nobuhiro Tanuma, Hiroshi Shima, Kenta Tsunekuni, Koichi Kawamoto, Naohiro Nishida, Jun Koseki, Koshi Mimori, Noriko Gotoh, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 111 ( 43 ) page: 15526 - 31   2014.10

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    Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-β-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-β signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.

    DOI: 10.1073/pnas.1407717111

    PubMed

  66. MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer Reviewed

    S. Hasegawa, H. Eguchi, H. Nagano, M. Konno, Y. Tomimaru, H. Wada, N. Hama, K. Kawamoto, S. Kobayashi, N. Nishida, J. Koseki, T. Nishimura, N. Gotoh, S. Ohno, N. Yabuta, H. Nojima, M. Mori, Y. Doki, H. Ishii

    BRITISH JOURNAL OF CANCER   Vol. 111 ( 8 ) page: 1572 - 1580   2014.10

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    Background: Pancreatic cancer has a poor prognosis because of its high refractoriness to chemotherapy and tumour recurrence, and these properties have been attributed to cancer stem cells (CSCs). MicroRNA (miRNA) regulates various molecular mechanisms of cancer progression associated with CSCs. This study aimed to identify the candidate miRNA and to characterise the clinical significance.
    Methods: We established gemcitabine-resistant Panc1 cells, and induced CSC-like properties through sphere formation. Candidate miRNAs were selected through microarray analysis. The overexpression and knockdown experiments were performed by evaluating the in vitro cell growth and in vivo tumourigenicity. The expression was studied in 24 pancreatic cancer samples after laser captured microdissection and by immunohistochemical staining.
    Results: The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR-1246 expression via CCNG2. In vivo, we found that miR-1246 could increase tumour-initiating potential and induced drug resistance. A high expression level of miR-1246 was correlated with a worse prognosis and CCNG2 expression was significantly lower in those patients.
    Conclusions: miR-1246 expression was associated with chemoresistance and CSC-like properties via CCNG2, and could predict worse prognosis in pancreatic cancer patients.

    DOI: 10.1038/bjc.2014.454

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  67. 骨肉腫細胞中のプロテアソーム活性の低い集団は癌幹細胞様特性を持つ(A small fraction of osteosarcoma cells with low proteasome activity have cancer stem-like properties) Reviewed

    玉利 慶介, 石井 秀始, 林 和彦, 今野 雅允, 川本 弘一, 西田 尚弘, 小関 準, 加納 義浩, 福角 隆仁, 土岐 祐一郎, 森 正樹, 小川 和彦

    日本癌学会総会記事   Vol. 73回   page: J - 2087   2014.9

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  68. Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase-E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis. Reviewed International journal

    Atsushi Hamabe, Hirofumi Yamamoto, Masamitsu Konno, Mamoru Uemura, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Naohiro Nishida, Koichi Kawamoto, Jun Koseki, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    Cancer science   Vol. 105 ( 9 ) page: 1100 - 8   2014.9

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    Although numerous studies have shown the significance of cancer-specific aerobic glycolysis, how glycolysis contributes to tumor invasion, a critical phenomenon in metastasis, remains unclear. With regard to colorectal cancer (CRC), we studied two critical gate enzymes, hexokinase 2 (HK2), which is involved in glycolysis, and phosphorylated pyruvate dehydrogenase-E1α (p-PDH), which is involved in oxidative phosphorylation (OxPhos). Immunohistochemical analyses using anti-HK2 and p-PDH antibodies were performed on surgically resected CRC samples (n = 104), and the expression in invasive front lesions of tumors was assessed. Positive HK2 expression correlated with extensive tumor diameter (P = 0.0460), advanced tumor depth (P = 0.0395), and presence of lymph node metastasis (P = 0.0409). Expression of p-PDH tended to be higher in right-sided CRCs than in left-sided CRCs (P = 0.0883). In survival analysis, the combined evaluation of positive HK2 and negative p-PDH was associated with reduced recurrence-free survival (RFS) (P = 0.0169 in all stages and P = 0.0238 in Stage II and III patients, respectively). This evaluation could predict RFS more precisely than the independent evaluation. The present study indicated that high HK2 expression combined with low p-PDH expression in the invasive front lesions of CRC tumors is predictive of tumor aggressiveness and survival of CRC cases.

    DOI: 10.1111/cas.12487

    PubMed

  69. プロテアソーム活性の低い甲状腺癌細胞は治療抵抗性・癌幹細胞の特質を持つ(Thyroid cancer cells with low proteasome activity have therapeutic resistance) Reviewed

    福角 隆仁, 石井 秀始, 今野 雅允, 西田 尚弘, 小関 準, 小川 久貴, 長谷川 慎一郎, 浜部 敦史, 林 和彦, 玉利 慶介, 土岐 祐一郎, 森 正樹, 猪原 秀典

    日本癌学会総会記事   Vol. 73回   page: J - 1033   2014.9

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  70. 子宮頸癌における癌幹細胞の可視化に関する研究(Optical imaging of cancer stem-like cells in cervical cancer) Reviewed

    林 和彦, 石井 秀始, 玉利 慶介, 今野 雅充, 川本 弘一, 西田 尚弘, 小関 準, 加納 義浩, 福角 隆仁, 土岐 雄一郎, 森 正樹, 小川 和彦

    日本癌学会総会記事   Vol. 73回   page: P - 1171   2014.9

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  71. 大腸癌先進部でのHexokinase 2とリン酸化型pyruvate dehydrogenase E1αの発現強度を複合解析することで予後不良群を鋭敏に予測できる Reviewed

    浜部 敦史, 山本 浩文, 今野 雅允, 植村 守, 西村 潤一, 畑 泰司, 竹政 伊知朗, 水島 恒和, 西田 尚弘, 川本 弘一, 小関 準, 土岐 祐一郎, 森 正樹, 石井 秀始

    日本分子腫瘍マーカー研究会プログラム・講演抄録   Vol. 34回   page: 56 - 57   2014.9

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  72. Murine Insulinoma Cell-Conditioned Medium with ΒETA2/Neurod1 Transduction Efficiently Induces the Differentiation of Adipose-Derived Mesenchymal Stem Cells into β-Like Cells both In Vitro and In Vivo Reviewed

    K. Kawamoto, S. Yabe, M. Konno, H. Ishii, N. Nishida, J. Koseki, S. Fukuda, Y. Tomimaru, N. Hama, H. Wada, S. Kobayashi, H. Eguchi, M. Tanemura, T. Ito, E. Y. Lee, E. Mukai, T. Miki, Y. Doki, M. Mori, T. S. Hamazaki, H. Nagano, H. Okochi

    Journal of Stem Cell Research & Therapy   Vol. 4 ( 8 ) page: 1000221   2014

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  73. Theoretical Study of the Substituent Effect on the Electronic Excited States of Chromophore in Cyan Fluorescent Proteins Reviewed

    Marina Takahashi, Jun Koseki, Yukiumi Kita, Yukio Kawashima, Masanori Tachikawa

    CHINESE JOURNAL OF PHYSICS   Vol. 51 ( 6 ) page: 1336 - 1350   2013.12

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    We performed ab initio molecular orbital and density functional theory calculations for enhanced cyan fluorescent protein, gold fluorescent protein, and (4-Me)-tryptophan enhanced cyan fluorescent protein to elucidate the substituent effect on the electronic structure of the chromophore in the fluorescent proteins. The electron correlation effect on the electronic structures is investigated as well. Our calculated excitation and deexcitation energies reasonably reproduce the corresponding experimental values. The qualitative Stokes shifts for the three fluorescent proteins were realized taking the electronic correlation into account. We found that the amino group of the chromophore in gold fluorescent protein enhances charge transfer among the ground and excited states, while the substituent effect of the methyl group, which is a weak electron donor, in (4-Me)-tryptophan enhanced cyan fluorescent protein was small. The charge transfer is the origin of the Stokes shift found in gold fluorescent protein. Thus, we succeeded in elucidating the substituent effect on the electronic structure of the chromophore in three fluorescent proteins.

    Web of Science

  74. Observation of the controlled assembly of preclick components in the in situ click chemistry generation of a chitinase inhibitor Reviewed

    Tomoyasu Hirose, Nobuo Maita, Hiroaki Gouda, Jun Koseki, Tsuyoshi Yamamoto, Akihiro Sugawara, Hirofumi Nakano, Shuichi Hirono, Kazuro Shiomi, Takeshi Watanabe, Hisaaki Taniguchi, K. Barry Sharpless, Satoshi Omura, Toshiaki Sunazuka

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 110 ( 40 ) page: 15892 - 15897   2013.10

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    The Huisgen cycloaddition of azides and alkynes, accelerated by target biomolecules, termed "in situ click chemistry,"has been successfully exploited to discover highly potent enzyme inhibitors. We have previously reported a specific Serratia marcescens chitinase B (SmChiB)-templated syn-triazole inhibitor generated in situ from an azide-bearing inhibitor and an alkyne fragment. Several in situ click chemistry studies have been reported. Although some mechanistic evidence has been obtained, such as X-ray analysis of [ protein]-["click ligand"] complexes, indicating that proteins act as both mold and template between unique pairs of azide and alkyne fragments, to date, observations have been based solely on "postclick" structural information. Here, we describe crystal structures of SmChiB complexed with an azide ligand and an O-allyl oxime fragment as a mimic of a click partner, revealing a mechanism for accelerating syn-triazole formation, which allows generation of its own distinct inhibitor. We have also performed density functional theory calculations based on the X-ray structure to explore the acceleration of the Huisgen cycloaddition by SmChiB. The density functional theory calculations reasonably support that SmChiB plays a role by the cage effect during the pretranslation and posttranslation states of selective syn-triazole click formation.

    DOI: 10.1073/pnas.1315049110

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    PubMed

  75. Temperature dependence of self-assembled molecular capsules consisting of gear-shaped amphiphile molecules with molecular dynamics simulations Reviewed

    Jun Koseki, Yukiumi Kita, Shuichi Hiraoka, Umpei Nagashima, Masanori Tachikawa

    INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY   Vol. 113 ( 4 ) page: 397 - 400   2013.2

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    Molecular dynamics simulations of hexameric molecular capsules constructed from gear-shaped amphiphile molecules with the aid of solvophobic effect and van der Waals force were performed with general AMBER force field to elucidate the thermodynamical properties of the capsules. The optimized structure of the capsule 16 consisting of methylated gear-shaped molecules (1) is a nearly cubic structure, whereas the distorted structure is found for the capsule 26 consisting of ones lacking three methyl groups, (2) so as to maximize the contact surface. Disassembly temperature for the demethylated capsule 26, similar to 210 K, is much lower than that for the methylated one 16, similar to 340 K, which is consistent with the corresponding experimental result that 16 is stable, whereas 2 exists as a monomer in aqueous methanol. (C) 2012 Wiley Periodicals, Inc.

    DOI: 10.1002/qua.24108

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  76. alpha-1-C-Butyl-1,4-dideoxy-1,4-imino-L-arabinitol as a Second-Generation Iminosugar-Based Oral alpha-Glucosidase Inhibitor for Improving Postprandial Hyperglycemia Reviewed

    Atsushi Kato, Erina Hayashi, Saori Miyauchi, Isao Adachi, Tatsushi Imahori, Yoshihiro Natori, Yuichi Yoshimura, Robert J. Nash, Hideyuki Shimaoka, Izumi Nakagome, Jun Koseki, Shuichi Hirono, Hiroki Takahata

    JOURNAL OF MEDICINAL CHEMISTRY   Vol. 55 ( 23 ) page: 10347 - 10362   2012.12

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    We report on the synthesis and the biological evaluation of a series of alpha-1-C-alkylated 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring-closing metathesis, and Negishi cross-coupling as key reactions. alpha-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 mu M, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of alpha-1-C-butyl-LAB and miglitol are clearly different. Furthermore, a-l-C-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. alpha-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia.

    DOI: 10.1021/jm301304e

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  77. Design, synthesis, and biological evaluation of novel (1-thioxo-1,2,3,4-tetrahydro-beta-carbolin-9-yl)acetic acids as selective inhibitors for AKR1B1 Reviewed

    Daisuke Minehira, Daisuke Takeda, Hirokazu Urata, Atsushi Kato, Isao Adachi, Xu Wang, Yuji Matsuya, Kenji Sugimoto, Mayuko Takemura, Satoshi Endo, Toshiyuki Matsunaga, Akira Hara, Jun Koseki, Kayo Narukawa, Shuichi Hirono, Naoki Toyooka

    BIOORGANIC & MEDICINAL CHEMISTRY   Vol. 20 ( 1 ) page: 356 - 367   2012.1

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    New substituted (1-thioxo-1,2,3,4-tetrahydro-b-carbolin-9-yl) acetic acids were designed as the inhibitor of AKR1B1 based upon the structure of rhetsinine, a minor alkaloidal component of Evodia rutaecarpa, and twenty derivatives were synthesized and evaluated. The most active compound of the series was (2-benzyl-6-methoxy-1-thioxo-1,2,3,4-tetrahydro-b-carbolin-9-yl) acetic acid (7m), which showed comparable inhibitory activity for AKR1B1 (IC50 = 0.15 mu M) with clinically used epalrestat (IC50 = 0.1 mu M). In the view of activity and selectivity, the most potent compound was (2-benzyl-6-carboxy-1-thioxo1,2,3,4-tetrahydro-b-carbolin-9-yl) acetic acid (7t), which showed strong inhibitory effect (IC50 = 0.17 mu M) and very high selectivity for AKR1B1 against AKR1A1 (311: 1) and AKR1B10 (253: 1) compared with epalrestat. (C) 2011 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.bmc.2011.10.073

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  78. Role of CH-pi interaction energy in self-assembled gear-shaped amphiphile molecules: correlated ab initio molecular orbital and density functional theory study Reviewed

    Jun Koseki, Yukiumi Kita, Shuichi Hiraoka, Umpei Nagashima, Masanori Tachikawa

    THEORETICAL CHEMISTRY ACCOUNTS   Vol. 130 ( 4-6 ) page: 1055 - 1059   2011.12

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPRINGER  

    Ab initio molecular orbital and density functional theory calculations with inclusion of dispersion interaction effect are employed to reveal the characteristic features of intermolecular interactions for the molecular capsule (1 (6)) consisting of six gear-shaped amphiphile molecules (1) discovered by Hiraoka et al. (J Am Chem Soc 130:14368-14369, 2008). The contributions of CH-pi and pi-pi type dispersion energies are found to be indispensable for the formation of hexameric capsule 1 (6) by the analysis of decomposed interaction energies between fragmented-model species in the 1 molecule. We have also calculated the hexameric capsule (2 (6)) from demethylated 1 molecule (2). Such subtle structural difference induces the different characters of intermolecular interactions, in which the stabilization energy of hexameric 2 (6) capsule is about 40 kcal/mol smaller than that of the original 1 (6) capsule, due to the lack of three methyl groups for the CH-pi interactions in 2 molecules.

    DOI: 10.1007/s00214-011-1053-2

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  79. Molecular Dynamics Simulation for Irreversibility of Green Fluorescent Protein before and after Photoactivation Reviewed

    Jun Koseki, Yukiumi Kita, Masanori Tachikawa

    CHEMISTRY LETTERS   Vol. 40 ( 5 ) page: 476 - 477   2011.5

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    To elucidate the irreversible photoreaction of green fluorescent protein (GFP), we have theoretically analyzed hydrogen-bonding networks and distributions of water molecules around a chromophore (CRO) of GFP before and after photoactivation. Our molecular dynamics simulation clearly shows that such irreversibility arises from the migration of water molecules to the hollowed out region due to the reorientation of amino acid residues together with the disappearance of hydrogen-bonding networks around the CRO.

    DOI: 10.1246/cl.2011.476

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  80. Theoretical study of the reversible photoconversion mechanism in Dronpa Reviewed

    Jun Koseki, Yukiumi Kita, Umpei Nagashima, Masanori Tachikawa

    PROCEEDINGS OF THE INTERNATIONAL CONFERENCE ON COMPUTATIONAL SCIENCE (ICCS)   Vol. 4   page: 251 - 260   2011

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    Authorship:Lead author   Language:English   Publishing type:Research paper (international conference proceedings)   Publisher:ELSEVIER SCIENCE BV  

    We propose a new scheme of the photoactivation and the photobleaching for Dronpa with molecular dynamics method and density functional theory. These processes can be explained by considering cis-trans isomerization in neutral state of chromophore. The proton transfer from anionic to neutral chromophore makes cis-trans isomerization possible via hula-twist rotation process, since the space for cis-trans isomerization is opened at around the region near chromophore by moving out of the imidazole ring on H193 from the position below the phenol ring on chromophore. Then the cis-trans isomerization can occur through the hula-twist process. The contributions from the protein environment around CRO, especially S142 and H193, are indispensable for photoconversion of Dronpa.

    DOI: 10.1016/j.procs.2011.04.027

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  81. Formation of Schiff-base for photoreaction mechanism of red shift of GFP spectra Reviewed

    Jun Koseki, Yukiumi Kita, Masanori Tachikawa

    BIOPHYSICAL CHEMISTRY   Vol. 147 ( 3 ) page: 140 - 145   2010.4

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER SCIENCE BV  

    We have proposed the formation of Schiff-base between R96 and chromophore (CRO) to elucidate the reaction mechanism for the irreversible red shift of green fluorescent protein (GFP) spectra under the absence of oxygen. The difference between absorption energies of reactant and product for our GFP models with CIS(D)/6-31G* level is 0.21 eV, which is in reasonable agreement with the corresponding experimental value of 0.25 eV. We have suggested the irreversible photoreaction mechanism, where the CRO excited from ground (S(0)) state to first excited singlet (S(1)) state immediately turns to the first excited triplet (T(1)) state, and the nucleophilic addition reaction occurs on the T(1) state. (C) 2010 Elsevier ay. All rights reserved.

    DOI: 10.1016/j.bpc.2010.01.008

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    PubMed

  82. 1P082 Formation of Schiff-base for photoreaction mechanism of red shift of GFP spectra(Protein:Function,The 48th Annual Meeting of the Biophysical Society of Japan) Reviewed

    Koseki Jun, Kita Yukiumi, Tachikawa Masanori

    Seibutsu Butsuri   Vol. 50 ( 2 ) page: S33   2010

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    DOI: 10.2142/biophys.50.S33_5

  83. Theoretical Analysis of Molecular Orientational Transition in Solid C60 Reviewed

    Y.Kita, J.Koseki, I.Okada

    Journal of Computer Chemistry, Japan   Vol. 9 ( 1 ) page: 55 - 60   2009.9

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    DOI: 10.2477/jccj.H2118M

  84. Quantum Monte Carlo study of porphyrin transition metal complexes Reviewed

    Jun Koseki, Ryo Maezono, Masanori Tachikawa, M. D. Towler, R. J. Needs

    JOURNAL OF CHEMICAL PHYSICS   Vol. 129 ( 8 ) page: 085103   2008.8

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER INST PHYSICS  

    Diffusion quantum Monte Carlo (DMC) calculations for transition metal (M) porphyrin complexes (MPo, M = Ni, Cu, Zn) are reported. We calculate the binding energies of the transition metal atoms to the porphin molecule. Our DMC results are in reasonable agreement with those obtained from density functional theory calculations using the B3LYP hybrid exchange-correlation functional. Our study shows that such calculations are feasible with the DMC method. (C) 2008 American Institute of Physics.

    DOI: 10.1063/1.2966003

    Web of Science

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Books 3

  1. 腫瘍免疫-免疫ネットワークから考える基礎と臨床-

    小関 準( Role: Contributor ,  がんゲノム医療と免疫治療の現状と展望)

    医歯薬出版株式会社  2022 

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    Responsible for pages:561-565   Language:Japanese Book type:Textbook, survey, introduction

  2. BIO EX-press

    ( Role: Contributor)

    2016 

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    Language:Japanese

  3. 膵島の再生医療

    小関 準( Role: Contributor ,  インシリコ創薬の現状と展望)

    診断と治療社  2015.2 

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    Language:Japanese

MISC 27

  1. 大腸がんにおけるヒストン脱メチル化酵素N066の臨床的意義の解明

    西沢佑次郎, 西田尚弘, 西田尚弘, 今野雅允, 今野雅允, 川本弘一, 小関準, 浅井歩, 浅井歩, 西村潤一, 畑泰司, 松田宙, 佐藤太郎, 水島恒和, 水島恒和, 山本浩文, 山本浩文, 土岐祐一郎, 森正樹, 石井秀始, 石井秀始

    日本がん転移学会学術集会・総会プログラム抄録集   Vol. 26th   page: 105   2017

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    J-GLOBAL

  2. ミトコンドリア葉酸代謝を標的とした新規抗癌剤のシステム的創薬展開

    浅井 歩, 小関 準, 今野 雅允, 西田 尚弘, 川本 弘一, 三代 雅明, 野口 幸蔵, 佐藤 太郎, 土岐 祐一郎, 森 正樹, 石井 秀始

    日本癌学会総会記事   Vol. 75回   page: J - 3075   2016.10

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  3. 大腸癌の飢餓ストレスに適応した代謝変化

    今野 雅允, 三代 雅明, 西田 尚弘, 川本 弘一, 小関 準, 土岐 祐一郎, 森 正樹, 石井 秀始

    日本癌学会総会記事   Vol. 75回   page: J - 3095   2016.10

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  4. TCAサイクル非依存的大腸癌細胞の代謝制御機構の解明

    今野雅允, 三代雅明, 西田尚弘, 西田尚弘, 川本弘一, 川本弘一, 小関準, 土岐祐一郎, 森正樹, 石井秀始

    がんと代謝研究会プログラム&amp;抄録集   Vol. 4th   page: 75   2016.7

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    J-GLOBAL

  5. ミトコンドリア内の葉酸代謝に着目した新規抗癌剤のシステム創薬展開

    浅井歩, 小関準, 今野雅允, 西田尚弘, 川本弘一, 三代雅明, 野口幸蔵, 佐藤太郎, 土岐雄一郎, 森正樹, 石井秀始

    がんと代謝研究会プログラム&amp;抄録集   Vol. 4th   page: 79   2016.7

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    J-GLOBAL

  6. Thermodynamic and molecular orbital analysis of the effects caused by incorporation of novel anti-tumor agent Trifluridine to DNA

    Jun Koseki, Kenta Tsunekuni, Masamitsu Konno, Naohiro Nishida, Koichi Kawamoto, Yuichiro Doki, Masaki Mon, Hideshi Ishii

    CANCER RESEARCH   Vol. 76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-2706

    Web of Science

  7. ミトコンドリアC1代謝を標的とした新規抗癌剤のシステム的創薬展開

    浅井 歩, 小関 準, 今野 雅允, 西田 尚弘, 川本 弘一, 三代 雅明, 野口 幸蔵, 佐藤 太郎, 土岐 雄一郎, 森 正樹, 石井 秀始

    ハイパフォーマンスコンピューティングと計算科学シンポジウム論文集   ( 2016 ) page: 53 - 53   2016.5

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  8. Molecular Targeting B-RAF Mutant Colorectal Cancer: Novel AMPK-induced Autophagy Mechanism

    T. Sueda, D. Sakai, K. Kawamoto, M. Konno, N. Nishida, J. Koseki, H. Takahashi, N. Haraguchi, J. Nishimura, T. Hata, I. Takemasa, T. Mizushima, H. Yamamoto, T. Sato, H. Ishii, Y. Doki, M. Mori

    ANNALS OF SURGICAL ONCOLOGY   Vol. 23   page: S79 - S79   2016.2

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    Web of Science

  9. The Role of Glutaminase C and Glutamine Metabolism in Epithelial-Mesenchymal Transition in Colorectal Cancer

    H. Colvin, N. Nishida, J. Koseki, M. Konno, K. Kawamoto, Y. Doki, M. Mori, H. Ishii

    ANNALS OF SURGICAL ONCOLOGY   Vol. 23   page: S84 - S84   2016.2

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    Web of Science

  10. microRNA遺伝子導入による大腸癌の悪性度低下の誘導

    俊山礼志, 江口英利, 小川久貴, 今野雅允, 川本弘一, 西田尚弘, 小関準, 野田剛広, 山田大作, 浅岡忠史, 和田浩志, 後藤邦仁, 山本浩文, 水島恒和, 石井秀始, 土岐祐一郎, 森正樹

    日本外科学会定期学術集会(Web)   Vol. 116th   page: OP‐091‐2 (WEB ONLY)   2016

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    J-GLOBAL

  11. マイクロRNAが関わる大腸癌治療抵抗性獲得メカニズムの解明

    西沢佑次郎, 西田尚弘, 今野雅充, 小関準, 川本弘一, 高橋秀和, 原口直紹, 西村潤一, 畑泰司, 竹政伊知朗, 水島恒和, 三森功士, 石井秀始, 山本浩文, 土岐祐一郎, 森正樹

    日本外科学会定期学術集会(Web)   Vol. 116th   page: PS‐138‐8 (WEB ONLY)   2016

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    J-GLOBAL

  12. One Carbon代謝を標的とする創薬の加速化

    浅井歩, 小関準, 今野雅允, 西田尚弘, 川本弘一, 三代雅明, 佐藤太郎, 土岐祐一郎, 土岐祐一郎, 土岐祐一郎, 森正樹, 森正樹, 森正樹, 石井秀始, 石井秀始

    日本分子生物学会年会プログラム・要旨集(Web)   Vol. 39th   page: ROMBUNNO.3AS9‐3(3P‐0886) (WEB ONLY)   2016

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    J-GLOBAL

  13. 臨床情報が裏付けるノンコーディングRNAエピゲノム修飾の意義

    西田尚弘, 大房健, 山縣彰, 小関準, 今野雅允, 川本弘一, 浅井歩, 水島恒和, 江口英利, 瀧口修司, 佐藤太郎, 三森功士, 落谷孝広, 土岐祐一郎, 森正樹, 石井秀始

    日本分子生物学会年会プログラム・要旨集(Web)   Vol. 39th   page: ROMBUNNO.2P‐0695 (WEB ONLY)   2016

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    J-GLOBAL

  14. Catch Up分子生物学 癌における解糖系酵素の制御とその働き

    浜部 敦史, 山本 浩文, 今野 雅允, 植村 守, 西村 潤一, 畑 泰司, 竹政 伊知朗, 水島 恒和, Colvin Hugh, 西田 尚弘, 川本 弘一, 小関 準, 土岐 祐一郎, 森 正樹, 石井 秀始

    大腸がんperspective   Vol. 2 ( 3 ) page: 217 - 221   2015.11

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    癌細胞に特有の糖代謝システムであるWarburg効果は、糖代謝関連酵素の発現・活性が変化することによって維持されている。ヘキソキナーゼ2(HK2)および非活性型ピルビン酸デヒドロゲナーゼ(PDH)の上昇は、それぞれ解糖促進およびクエン酸回路への流入阻害を介して、Warburg効果形成に寄与している。最近報告されたHK2およびPDHの研究により、これらの酵素の詳細な機能が検討され、酵素を標的とする治療が有効である可能性が示された。しかし、癌における代謝システムが、癌細胞が浸潤する過程においてどのような意義をもつかはこれまで明らかとされていない。浸潤において、癌細胞は上皮間葉転換(EMT)という細胞レベルの変化を受けて、間葉系形質を獲得するが、われわれの研究によりEMT変化がHK2上昇および活性型PDHの上昇を伴うことが示された。癌における代謝の機能は不明な点が数多く存在し、これらを明らかにしていくことで新規治療の確立へとつながることが期待される。(著者抄録)

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J06465&link_issn=&doc_id=20151030120007&doc_link_id=%2Fai1cocad%2F2015%2F000203%2F009%2F0217-0221%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1cocad%2F2015%2F000203%2F009%2F0217-0221%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  15. 大腸癌におけるSIRT4の腫瘍抑制因子としての機能

    三代 雅明, 今野 雅允, 山本 浩文, 浜部 敦史, 竹政 伊知朗, 水島 恒和, 小関 準, 川本 弘一, 西田 尚弘, 土岐 祐一郎, 森 正樹, 石井 秀始

    日本癌学会総会記事   Vol. 74回   page: P - 1324   2015.10

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  16. Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer

    Jun Koseki, Hugh Colvin, Takahito Fukusumi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    CANCER RESEARCH   Vol. 75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-4583

    Web of Science

  17. Role of nuclear PKM2 in transcriptional regulation leading to EMT

    Masamitsu Konno, Naohiro Nishida, Koichi Kawamoto, Jun Koseki, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    CANCER RESEARCH   Vol. 75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-4080

    Web of Science

  18. Microarray analysis of radioresistant mouse squamous cell carcinoma: comparison of x-ray resistance and carbon-ion beam resistance

    Sungjae Baek, Hideshi Ishii, Katsutoshi Sato, Naohiro Nishida, Keisuke Tamari, Kazuhiko Hayashi, Yuji Seo, Koichi Kawamoto, Jun Koseki, Masamitsu Konno, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa

    CANCER RESEARCH   Vol. 75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-3334

    Web of Science

  19. KDM5B plays a central role in esophageal cancer progression

    Naohiro Nishida, Yoshihiro Kano, Jun Koseki, Masamitsu Konno, Koichi Kawamoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii

    CANCER RESEARCH   Vol. 75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-102

    Web of Science

  20. Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase E1α in invasive front lesions of colorectal tumors

    Hamabe Atsushi, Kawamoto Koichi, Koseki Jun, Doki Yuichiro, Mori Masaki, Ishii Hideshi, Yamamoto Hirofumi, Konno Masamitsu, Uemura Mamoru, Nishimura Junichi, Hata Taishi, Takemasa Ichiro, Mizushima Tsunekazu, Nishida Naohiro

    Japan Journal of Molecular Tumor Marker Research   Vol. 30 ( 0 ) page: 37 - 38   2015

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  21. Significance of KRAS in Glutamine Metabolism of Colorectal Cancer

    Miyo Masaaki, Doki Yuichiro, Mori Masaki, Ishii Hideshi, Konno Masamitsu, Yamamoto Hirofumi, Hamabe Atsushi, Takemasa Ichiro, Mizushima Tsunekazu, Koseki Jun, Kawamoto Koichi, Nishida Naohiro

    Japan Journal of Molecular Tumor Marker Research   Vol. 30 ( 0 ) page: 39 - 40   2015

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  22. Biological properties of CD24 as a marker for epithelial-mesenchymal transition in human colorectal cancer stem cell

    Hata Tsuyoshi, Mori Masaki, Doki Yuichiro, Ishii Hideshi, Yamamoto Hirofumi, Okano Miho, Konnno Masamitsu, Nishida Naohiro, Koseki Jun, Kawamoto Koichi, Takemasa Ichiro, Mizushima Tsunekazu

    Japan Journal of Molecular Tumor Marker Research   Vol. 30 ( 0 ) page: 19 - 20   2015

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  23. Nuclear pyruvate kinase M2 regulates epithelial-mesenchymal transition by controlling E-cadherin expression.

    A. Hamabe, M. Konno, H. Yamamoto, T. Mizushima, I. Takemasa, N. Tanuma, H. Shima, N. Nishida, J. Koseki, K. Kawamoto, Y. Doki, M. Mori, H. Ishii

    MOLECULAR BIOLOGY OF THE CELL   Vol. 25   2014.12

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  24. 腫瘍をめぐるQ&A(Question74) VEGFとEMT・癌幹細胞との関連について

    小川 久貴, 山本 浩文, 今野 雅允, 川本 弘一, 西田 尚弘, 小関 準, 浜部 敦史, 長谷川 慎一郎, 福角 隆仁, 林 和彦, 玉利 慶介, 土岐 祐一郎, 森 正樹, 石井 秀始

    Surgery Frontier   Vol. 21 ( 4 ) page: 402 - 405   2014.12

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  25. 大腸癌幹細胞における上皮間葉移行(EMT)マーカーとしてのCD24の生物学的特性

    波多豪, 山本浩文, 岡野美穂, 今野雅允, 西田尚弘, 小関準, 川本弘一, 竹政伊知朗, 水島恒和, 森正樹, 土岐祐一郎, 石井秀始

    日本分子腫瘍マーカー研究会プログラム・講演抄録   Vol. 34th   page: 38 - 39   2014.9

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    J-GLOBAL

  26. 大腸癌細胞のグルタミン代謝におけるKRAS遺伝子の意義

    三代雅明, 今野雅允, 山本浩文, 浜部敦史, 竹政伊知朗, 水島恒和, 小関準, 川本弘一, 西田尚弘, 土岐祐一郎, 森正樹, 石井秀始

    日本分子腫瘍マーカー研究会プログラム・講演抄録   Vol. 34th   page: 58 - 59   2014.9

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    J-GLOBAL

  27. 大腸癌細胞のグルタミン代謝におけるKRAS遺伝子の意義(Significance of KRAS in Glutamine Metabolism of Colorectal Cancer)

    三代 雅明, 今野 雅允, 山本 浩文, 浜部 敦史, 竹政 伊知朗, 水島 恒和, 小関 準, 川本 弘一, 西田 尚弘, 土岐 祐一郎, 森 正樹, 石井 秀始

    日本癌学会総会記事   Vol. 73回   page: J - 2044   2014.9

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Presentations 42

  1. トポロジカルデータ解析を用いた微小構造変化がもたらす構造及び相互作用変化解析 Invited

    小関準

    第6回理論免疫学ワークショップ  2022.3.12 

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    Event date: 2022.3

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:オンライン   Country:Japan  

  2. Theoretical prediction of molecular interaction changes caused by microstructural substitutions

    Jun Koseki

    2021.12.1 

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    Event date: 2021.12

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  3. アミノ酸変異によるタンパク質立体構造変化のトポロジカルデータ解析

    小関 準、小嶋 泰弘、林 周斗、廣瀬 遥香、南 賢河、島村 徹平

    第15回分子科学討論会  2021.9.18  分子科学会

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    Event date: 2021.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:北海道大学   Country:Japan  

  4. アミノ酸変異によるタンパク質立体構造変化の予測

    小関準

    社会実装を目指した異分野融合生物学  2021.7.14 

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    Event date: 2021.7

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:松本   Country:Japan  

  5. フッ素置換基を有した核酸分子が及ぼすDNA立体構造変化と内部相互作用変化に対する理論解析

    小関 準, 今野 雅允, 浅井 歩, 堀江 直宏, 常國 健太, 小比賀 聡, 石井 秀始

    第42回 日本分子生物学会  2019.12.4 

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    Event date: 2019.12

    Language:English   Presentation type:Poster presentation  

  6. p53タンパク質と任意の認識配列の結合構造及び結合親和性予測システムの確立

    小関準

    がんと代謝研究会・若手の会  2019.11.14 

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    Event date: 2019.11

    Language:English   Presentation type:Oral presentation (general)  

  7. An importance of polyamine metabolism regulated by cancer stem cells highlighted by our trans-omics method

    Jun Koseki, Masamitsu Konno, Ayumu Asai, Hideshi Ishii

    An importance of polyamine metabolism regulated by cancer stem cells highlighted by our trans-omics method  2019.10 

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    Event date: 2019.10

    Language:English   Presentation type:Poster presentation  

  8. Drug design and improvement study using theoretical science and machine learning for digestive system cancer therapy

    Jun Koseki, Masamitsu Konno, Yuichiro Doki, Hideshi Ishii

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    Event date: 2019.9

    Language:English   Presentation type:Poster presentation  

  9. The Analysis of Chemoresistance in Cancer Stem Cells Using a Novel Trans-omics Method

    J. Koseki, M. Konno, A. Asai, T. Satoh, Y. Doki, M. Mori, H. Ishii

    The Analysis of Chemoresistance in Cancer Stem Cells Using a Novel Trans-omics Method  2017.9.29 

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    Event date: 2017.9

    Language:English   Presentation type:Oral presentation (general)  

  10. トランス-オミックス法を用いたがん幹細胞におけるポリアミン代謝経路の意義の解析

    小関 準, 今野 雅允, 松井 秀俊, 加納 義弘, 佐藤 太郎, 森 正樹, 土岐 祐一郎, 石井 秀始

    癌転移学会  2017.7.27 

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    Event date: 2017.7

    Language:Japanese   Presentation type:Oral presentation (general)  

  11. がん幹細胞におけるオルニチン代謝経路のトランスオミックス解析

    小関 準, 今野 雅允, 浅井 歩, 松井 秀俊, 尾崎 みゆ希, 佐藤 太郎, 土岐 祐一郎, 森 正樹, 石井 秀始

    第5回がんと代謝研究会  2017.7.14 

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    Event date: 2017.7

    Language:Japanese   Presentation type:Poster presentation  

  12. トランス・オミックス解析によって抽出された、がん幹細胞の新しい機能 Invited

    小関 準

    第85回バイオメクフォーラム21  2017.7.8 

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    Event date: 2017.7

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  13. Trans-omics analysis shows novel functional change in the ornithine metabolic pathway between cancer stem cells and non-cancer stem cells Invited International conference

    J. Koseki, H. Matsui, M. Konno, N. Nishida, K. Kawamoto, Y. Kano, A. Asai, Y. Doki, M. Mori, H. Ishii

    The 26th Hot Spring Harbor International Symposium  2016.11.3 

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    Event date: 2016.11

    Language:English   Presentation type:Oral presentation (invited, special)  

  14. Trans-omics Analysis brings out Novel Functions of the Ornithine Metabolic Pathway in Cancer Stem Cells

    2016.10 

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    Event date: 2016.10

    Language:Japanese   Presentation type:Oral presentation (general)  

  15. トランスオミックス解析により見い出された、がん幹細胞におけるオルニチン代謝経路の新機能 Invited

    小関 準

    第3回次世代がんインフォマティクス研究会  2016.6.3 

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    Event date: 2016.6

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  16. Thermodynamic and molecular orbital analysis of the effects caused by incorporation of novel anti-tumor agent Trifluridine to DNA International conference

    J. Koseki, K. Tsunekuni, M. Konno, N. Nishida, K. Kawamoto, Y. Doki, M. Mori, H. Ishii

    AACR 2016  2016.4 

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    Event date: 2016.4

    Language:English   Presentation type:Poster presentation  

  17. Theoretical analysis of the effects caused by incorporation of Trifluridine to DNA International conference

    J. Koseki, K. Tsunekuni, M. Konno, N. Nishida, K. Kawamoto, Y. Doki, M. Mori, H. Ishii

    PACIFICHEM 2015  2015.12 

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    Event date: 2015.12

    Language:English   Presentation type:Poster presentation  

  18. Computational Analysis of the effects caused by incorporation of Trifluridine to DNA

    J. Koseki, K. Tsunekuni, M. Konno, N. Nishida, K. Kawamoto, Y. Doki, M. Mori, H. Ishii

    Computational Analysis of the effects caused by incorporation of Trifluridine to DNA  2015.10 

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    Event date: 2015.10

    Language:Japanese   Presentation type:Oral presentation (general)  

  19. Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer International conference

    J. Koseki, H. Colvin, T. Fukusumi, N. Nishida, M. Konno, K. Kawamoto, K. Tsunekuni, Y. Doki, M. Mori, H. Ishii

    AACR 2015  2015.4 

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    Event date: 2015.4

    Language:English   Presentation type:Poster presentation  

  20. 統計解析により予測される大腸がんにおけるIDH1/2不均衡発現の影響

    小関 準, Hugh Colvine, 福角 隆仁, 西田 尚弘, 今野 雅允, 川本 弘一, 常國 健太, 土岐 祐一郎, 森 正樹, 石井 秀始

    個体レベルでのがん研究の新展開  2015.2 

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    Event date: 2015.2

    Language:English   Presentation type:Oral presentation (general)  

  21. 数理解析が予測する大腸癌におけるIDH1/2不均衡発現の影響

    小関 準, Hugh Colvine, 福角 隆仁, 西田 尚弘, 今野 雅允, 川本 弘一, 常國 健太, 土岐 祐一郎, 森 正樹, 石井 秀始

    日本癌学会シンポジウム/共同利用・共同研究拠点シンポジウム  2015.1 

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    Event date: 2015.1

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

  22. Mathematical analysis predicts unbalanced IDH1/2 expression associate with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

    小関 準, 石井 秀始, 森 正樹

    「がん研究分野の特性等を踏まえた支援活動」公開シンポジウム  2015.1 

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    Event date: 2015.1

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

  23. Computational analysis predicts imbalanced IDH1/2 expression associate with 2-HG-inactivating β-oxygenation pathway in colorectal cancer International conference

    J. Koseki, H. Colvin, T. Fukusumi, N. Nishida, M. Konno, K. Kawamoto, K. Tsunekuni, Y. Doki, M. Mori, H. Ishii

    International Symposium on TGF-β and Cancer  2015.1 

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    Event date: 2015.1

    Language:English   Presentation type:Poster presentation  

  24. Computational analysis predicts imbalanced IDH1/2 expression associate with 2-HG-inactivating β- oxygenation pathway in colorectal cancer International conference

    J. Koseki, H. Colvin, T. Fukusumi, N. Nishida, M. Konno, K. Kawamoto, K. Tsunekuni, Y. Doki, M. Mori, H. Ishii

    Cell Symposia Stem Cell Energetics  2014.12 

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    Event date: 2014.12

    Language:English   Presentation type:Poster presentation  

  25. JARID1B Knockdown reduces gastroenterological cancer cell malignancy

    J. Koseki, K. Ohta, Y. Kano, M. Konno, N. Nishida, K. Kawamoto, K. Tsunekuni, H. Colvin, Y. Doki, M. Mori, H. Ishii

    2014 

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    Event date: 2014

    Language:Japanese   Presentation type:Poster presentation  

  26. Mathematical analysis predicts imbalanced IDH1/2 expression associate with 2-HG-inactivating beta- oxygenation pathway in colorectal cancer

    J Koseki, M. Konno, N. Nishida, K. Kawamoto, Y. Doki, M. Mori, H., Ishii

    Mathematical analysis predicts imbalanced IDH1/2 expression associate with 2-HG-inactivating beta- oxygenation pathway in colorectal cancer  2014 

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    Event date: 2014

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

  27. AKR阻害剤のサブファミリー選択性に関する計算化学的研究

    小関 準, 加藤 敦, 豊岡 尚樹, 広野 修一

    日本薬学会第132年会  2012.3 

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    Language:Japanese   Presentation type:Poster presentation  

  28. GFPスペクトルのRed Shiftメカニズムの解明

    小関 準, 北 幸海, 立川 仁典

    第48回 日本生物物理学会年会  2010.9 

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    Language:Japanese   Presentation type:Poster presentation  

  29. Dronpaの可逆的光変異機構に対する理論的研究

    小関 準, 北 幸海, 長嶋 雲兵, 立川 仁典

    日本化学会 第91回春季年会  2011.3 

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    Language:Japanese   Presentation type:Oral presentation (general)  

  30. GFPスペクトルのRed Shiftメカニズムの解明

    小関 準, 立川 仁典

    第2回分子化学討論会 2008  2008.9 

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    Language:Japanese   Presentation type:Poster presentation  

  31. 蛋白質芳香性疎水ポケットにおけるリガンド分子内水素結合形成に関する計算化学的研究

    小関 準, 合田 浩明, 広野 修一

    第35回情報科学討論会  2012.10.5 

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    Language:Japanese   Presentation type:Poster presentation  

  32. 芳香性クラスターのタンパク-リガンド相互作用への寄与

    山﨑 広之, 小関 準, 西端 芳彦, 広野 修一

    第36回情報科学討論会  2013.11 

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    Language:Japanese   Presentation type:Poster presentation  

  33. 緑色蛍光タンパク質類似体 CFPとGdFPにおける蛍光特性に関する理論的研究

    高橋 麻里奈, 小関 準, 北 幸海, 立川 仁典

    第5回 分子科学討論会2011  2011.9 

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    Language:Japanese   Presentation type:Poster presentation  

  34. 緑色蛍光タンパク質変異体CFPとGdFPにおける光特性に関する理論的研究

    高橋 麻里奈, 小関 準, 北 幸海, 川島 雪生, 立川 仁典

    分子科学討論会2012  2012.9 

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    Language:Japanese   Presentation type:Poster presentation  

  35. タンパク質-タンパク質界面における荷電性アミノ酸残基と周辺残基との相互作用解析

    小関 準, 山﨑 広之, 西端 芳彦, 広野 修一

    第36回情報科学討論会  2013.11 

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    Language:Japanese   Presentation type:Poster presentation  

  36. Theoretical Study of the reversible photoconversion mechanism in Dronpa International conference

    J.Koseki, Y.Kita, U.Nagashima, M.Tachikawa

    5th symposium on Theoretical Biophysics  2011.6 

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    Language:English   Presentation type:Poster presentation  

  37. Theoretical Study of the reversible photoconversion mechanism in Dronpa International conference

    J.Koseki, Y.Kita, U.Nagashima, M.Tachikawa

    International Conference on Computational Science  2011.6 

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    Language:English   Presentation type:Oral presentation (general)  

  38. Sucrase及びIsomaltaseへのLAB化合物の結合様式に関する理論的研究

    小関 準, 中込 泉, 足立 伊佐雄, 加藤 敦, 広野 修一

    第40回構造活性相関シンポジウム  2012.11 

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    Language:Japanese   Presentation type:Poster presentation  

  39. Molecular Orbital Study on Red Shift of GFP Spectra International conference

    J. Koseki, M. Tachikawa

    13th ICQC (International Congress of Quantum Chemistry)  2009.6 

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    Language:English   Presentation type:Poster presentation  

  40. Molecular Orbital Study on Red Shift of GFP Spectra International conference

    Jun Koseki

    PACIFICHEM 2010  2010.12 

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    Language:English   Presentation type:Poster presentation  

  41. GFPスペクトルのRed Shiftメカニズムの解明

    小関 準, 立川 仁典

    第13回 理論化学討論会  2010.5 

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    Language:Japanese   Presentation type:Poster presentation  

  42. GFPスペクトルのRed Shiftメカニズムの解明

    小関 準, 立川 仁典

    日本化学会 第89回春季年会  2009.3 

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▼display all

KAKENHI (Grants-in-Aid for Scientific Research) 26

  1. Maternal factors in embryonic development; impact of maternal age

    Grant number:22H03042  2022.4 - 2026.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Coinvestigator(s) 

  2. Development of a theoretical basis for predicting structural and functional changes induced by RNA modifications

    Grant number:22H03686  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator 

    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

  3. NF-κBに依存しない自然免疫誘導メカニズムの解明

    Grant number:22H02570  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(B)

    倉石 貴透, 小関 準, 堀 亜紀

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    Authorship:Coinvestigator(s) 

    自然免疫はすべての多細胞生物が持つ生体防御機構である。自然免疫の働きはあらゆる感染症の防御に重要であるため、新型コロナウイルス感染症の重症化しやすさの違いも自然免疫の活性化程度の違いで一部説明できると考えられている。ところが近年、感染防御に働くはずの自然免疫が微生物非依存的に活性化し、慢性炎症や自己免疫疾患の引き金となることがわかってきた。しかし、自然免疫がいかにして無菌的に活性化されるか未だ解明されていない。そのため本研究では、自然免疫機構が哺乳類に類似したショウジョウバエを用いて、自然免疫が無菌的に活性化される仕組みを、特に転写因子NF-κBに依存しないメカニズムを中心に明らかにする。

  4. 脳内微小環境と癌細胞の相互作用を解明する異分野融合的解析法

    Grant number:21448326  2021 - 2022.3

    国立研究開発法人日本医療研究開発機構  次世代がん医療創生研究事業 

    辻 貴宏、小笹 裕晃、荒川 芳輝、小関 準

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    Authorship:Coinvestigator(s) 

    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

  5. BRCAnessの薬理学的誘導によるPARP阻害剤臨床用途の新たな開拓

    Grant number:21448118  2021 - 2022.3

    国立研究開発法人日本医療研究開発機構  次世代がん医療創生研究事業 

    日野原 邦彦、加藤 真一郎、小関 準

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    Authorship:Coinvestigator(s) 

    Grant amount:\1300000 ( Direct Cost: \1000000 、 Indirect Cost:\300000 )

  6. 野生型及び任意の変異型P53タンパク質が任意配列のDNAを認識・結合する効率を予測するシステムの確立

    2020.9

    武田化学振興財団  医学系研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000 ( Direct Cost: \2000000 )

  7. Elucidation of the relationship between cancer malignancy and RNA modification

    Grant number:19K07688  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s) 

    Grant amount:\195000 ( Direct Cost: \150000 、 Indirect Cost:\45000 )

  8. Development of artificial intelligence system to support postoperative chemotherapy

    Grant number:19K09172  2019.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s) 

    Grant amount:\130000 ( Direct Cost: \100000 、 Indirect Cost:\30000 )

  9. がん抑制タンパク質 p53のDNA認識予測システムの確立~p53変異と標的DNA変異が及ぼす認識効率への影響~

    2019.3 - 2020.3

    大阪対がん協会  がん研究助成奨励金 

    小関 準

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\300000

  10. Elucidation and application of early brain metastasis mechanism by Warburg regulator MPC

    Grant number:18K08704  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    KUDO Toshihiro

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    Authorship:Coinvestigator(s) 

    Brain metastases show strong treatment resistance, and the current situation is that current anticancer drugs, molecular-targeted therapies, and radiation therapy do not provide fundamental efficacy. Therefore, it is essential to elucidate the treatment resistance rooted in the true nature of cancer and to develop a treatment method. According to our research results, the regulation of anaerobic glycolysis by the key molecule MPC (mitochondrial pyruvate transporter) of the Warburg effect induces epithelial-mesenchymal transformation (EMT) to make cancer stem cells, and multiple It was revealed that the treatment resistance to the anticancer drug was acquired. For cancer cells that are relatively prone to brain metastasis as a mechanism, the role of MPC in early brain metastasis is investigated by single cells from the three-dimensional reconstruction of the cell group that constitutes the blood-brain barrier (BBB) toward the future clinical application.

  11. RNAのm6A修飾による翻訳機序を標的とした難治がんの画期的な創薬と応用

    2018.4 - 2020.3

    科学研究費補助金 

    小関準

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    Authorship:Principal investigator 

  12. Novel drug discovery and application of intractable cancer targeting RNA m6A modification

    Grant number:18K16356  2018.4 - 2020.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Koseki Jun

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    Subclass classification based on RNA methylation information was performed using surgically excised samples of intractable gastrointestinal cancer.
    Then, we constructed a platform for companion drug discovery by linking the methylation information of microRNA of peripheral blood.
    The effect of oncoprotein on the translation system was examined in 18 types of cancer cells. In addition, the effect of hit compounds on normal cells was examined by Run-On assay.

  13. AI画像解析とトランス・オミックス解析を組み合わせたがん細胞の抗がん剤耐性メカニズム解明

    2018 - 2019

    コニカミノルタ  コニカミノルタ画像科学奨励賞 

    小関 準

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\1000000 ( Direct Cost: \1000000 )

  14. 筋ジストロフィーモデルマウスを用いた疾患発症機序の解明

    2018 - 2019

    中冨健康科学振興財団  中冨健康科学振興財団 研究助成 

    小関 準

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\1500000

  15. 難治性消化器がんに対するエピゲノム創薬

    2017.10 - 2019.3

    大阪大学・田辺三菱製薬株式会社  産学連携プロジェクト MEET 

    小関 準

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2400000 ( Direct Cost: \2000000 、 Indirect Cost:\400000 )

  16. Grasp of tissue homeostasis by microRNA modomics and clinical application

    Grant number:17K19698  2017.6 - 2019.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Ishii Hideshi, MORI masaki, DOKI yuichiro, EGUCHI hidetoshi, TANIGUCHI masateru, KAWAMOTO koichi

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    Authorship:Coinvestigator(s) 

    There is no established technique for deciphering chemical modification at the single base level of microRNA. Two closely complementary techniques were applied to precisely profile the modality of total microRNAs. Accurate measurement of intramolecular modification by mass spectrometry, and accumulation of data of short sequence by tunneling current sequence (TS) method was performed. We studied a new viewpoint by advancing the modulomic analysis of single cell level microRNA by the above measurement technology to understand the mechanisms of tissue homeostasis. We studied the development and carcinogenesis of the pancreas using genetically modified mice of microRNA methylation enzymes, and proceeded to understand the role of RNA modus in carcinogenesis from somatic stem cells in human diseases.

  17. Foundation construction and clinical application of next-generation RNA biomarker

    Grant number:17H04282  2017.4 - 2020.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    ISHII Hideshi

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    Authorship:Coinvestigator(s) 

    MicroRNAs secreted in body fluids are useful as biomarkers of disease. For the first time in the world, we have developed a new technique for measuring methylation modification at a specific site on a microRNA sequence by mass spectrometry. In our pilot study, high performance over conventional biomarkers has been obtained in early diagnosis of gastrointestinal cancer including pancreatic cancer. Since the methylation of microRNAs reflects the epigenetic pathology of cellular tissues, highly accurate measurement results are extremely useful for early diagnosis and subclass classification. In this plan, we will make extensive use of this "core technology" to study gastrointestinal cancer and other diseases, and establish it as a biomarker for next-generation medicine based on "data science".

  18. 創薬プロファイリング技術を駆使したエピゲノム創薬の加速化と実現

    2016.4 - 2018.3

    文部科学省  科学研究費補助金(挑戦的萌芽研究) 

    小関 準

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    Authorship:Principal investigator  Grant type:Competitive

  19. Acceleration and satisfaction of epigenetic drug discovery using profiling technology

    Grant number:16K15616  2016.4 - 2018.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    KOSEKI Jyun, ISHII Hideshi

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    Authorship:Principal investigator 

    Grant amount:\3380000 ( Direct Cost: \2600000 、 Indirect Cost:\780000 )

    It was very difficult in the past to screen inhibitors of JARID1B, one of epigenome regulatory factor. We have made it possible using our in silico screening technologies with large-scale computer. In silico screening has been already performed to pick up the candidate compounds from five million drug like compounds. Then, we selected first lead compounds from the picked up candidate compounds with chemical assay. We have investigated the in vitro anti-cancer effects of these lead compounds, and the after, investigated the in vivo anti-cancer effects for the part of them. We succeeded in establishing a pathway to show the synthetic evolution guidelines for lead compounds based on the functional information from these experimental results. According to this procedure, it is possible to design a more efficient drug structure.

  20. A non-invasive tool for detecting pancreatic tumor-bearing murine odor by C. elegans

    Grant number:16K15591  2016.4 - 2018.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    KAWAMOTO Koichi, MORI Masaki, HIROTSU Takaaki, SUGIMOTO Masahiro

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    Authorship:Coinvestigator(s) 

    Diagnosis of pancreatic ductal adenocarcinoma is associated with dismal prognosis despite current best therapies, including surgery, chemoradiation, and immunotherapy. Previous studies reported that wild-type C. Elegans displayed attractive chemotaxis towards human urine from cancer patients but avoided control urine from healthy volunteers. In this study, our research group demonstrated that C. Elegans induces chemotactic properties to the urine from pancreatic tumor-bearing mice. Furthermore, urine from c-Met knockout has minimal effect to these chemotactic properties. These results suggest that urine from tumor-bearing mice could provide a new strategy to detect and study disease-associated scents in the future.

  21. New development of epigenome drug discovery to realize oncogene selectivity

    Grant number:16K15592  2016.4 - 2018.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    SATOH Taroh, ISHII Hideshi, MORI Masaki

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    Authorship:Coinvestigator(s) 

    To target an oncogene in clinical setting, it is important to develop effective drug discovery based on the accurate information in epigenome. In the present study, the histone demethylating enzyme controlled by oncogene c - MYC was identified as a target candidate by using the comprehensive transcriptome analysis method. As a result, it was shown that histone methylation modification system was important and that NO66 played an important role in gastrointestinal cancer as its target. Furthermore we showed that it was possible to overcome refractory cancer by drug discovery targeting MYC - NO 66, for which we constructed the foundation.

  22. Development of innovative nucleic acid medicine for gastroenterological cancer

    Grant number:16K15615  2016.4 - 2018.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    KONNO Masamitsu, OBIKA Satoshi, NISHIYAMA Nobuhiro, MORI Masaki

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    Authorship:Coinvestigator(s) 

    We designed 20 kinds of guide chain and a passenger chain based on natural sequence of miR302 or miR200c. 400 kinds of artificial nucleic acid medicine were elaborated. The arrangement expected that a RNase in the body could be endured based on the former experience was designed. A screening was performed and even about 3 kinds of the artificial building type miR302, 200c was narrowed down respectively. These nucleic acids were injected to natural pancreatic cancer and a colon cancer carcinogenic model mouse. The volume of the cancer was measured and a presence of adverse event was monitored. Finally we identified the most efficient artificial building type nucleic acid medicine.

  23. Development of chip device to detect methylations on microRNAs

    Grant number:15K15474  2015.4 - 2017.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    Nishida Naohiro, Mori Masaki, Obika Satoshi

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    Authorship:Coinvestigator(s) 

    Chemical modifications of microRNA molecules potentially alter their biological functions. This study is aimed for a development of devices to comprehensively detect methylations of small nucleotide molecules including microRNAs. Efficient purifications of target microRNAs and highly accurate detection using mass spectrometry are key processes of this system. We have developed target enrichment method using affinity chromatography to precisely quantify chemical modifications on microRNAs from a very few amount of RNA samples. Furthermore, the optimizations of mass spectrometry settings including improvement of ionization efficiency and adjustment of measurement ranges enabled detection of a very small amount of chemical modifications (less than 5%) on microRNA oligonucleotides. To detect variety kinds of chemical modifications on many microRNA species, we have designed chip devices, on which oligonucleotides with complement DNA sequence of target microRNAs are densely printed.

  24. Elucidation of epigenetic modification mechanisms of long non-coding RNAs

    Grant number:15K15475  2015.4 - 2017.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    Kudo Toshihiro, Ishii Hideshi, Mori Masaki

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    Authorship:Coinvestigator(s) 

    Chemical modifications on long non-coding RNA (lncRNA) molecules potentially alter their biological functions. In this study, we have demonstrated functional alterations of lncRNAs upon induction of chemical modifications, such as methylations and acetylations. We have started with a comprehensive profiling of hypoxia-induced long lncRNAs, which could be good candidates for key oncogenic molecules in cancer microenvironment. By using PCR-based microarray method, we identified several candidate lncRNAs. In vitro functional assays revealed these lncRNAs could play an important role in cancer progression. Knockdown of RNA methylation enzyme reduced methylation levels of lncRNA transcripts and lead to functional alterations including growth inhibition, resistance to chemotherapeutic agents. These findings suggest that chemical modifications on lncRNAs is crucially involved in cancer progression and that the methylation enzyme could be a crucial therapeutic target.

  25. New construction of in vivo reprogramming technology by modified microRNA

    Grant number:15K15496  2015.4 - 2017.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    ISHII Hideshi, Mori Masaki, Obika Satoshi, Nishiyama Nobuhiro

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    Authorship:Coinvestigator(s) 

    In order to optimize endogenous microRNAs expressed in embryonic phase as pharmaceuticals, crosslinked modification as covalent bonds and others and drug delivery system (DDS) have been constructed (patented). Applicable range embodies direct reprogramming of somatic cells including cancer cell culture in vitro and animal model in vivo. The innovative cell modification based on the epigenetic control by nucleotide medicine will be valuable for the construction of a new therapeutic strategy and innovative disease control, as well as acceleration to drug optimization and corporative relocation, towards the future clinical application.

  26. RNA安定化構造の理論予測システムの確立

    2015.4 - 2016.3

    大阪対がん教会  がん研究助成奨励金 

    小関 準

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\300000

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Teaching Experience (On-campus) 3

  1. 基盤医科学実習 CIBoG Linux及びBash入門/次世代シークエンス解析入門

    2022

  2. 基盤医科学実習 CIBoG Linux及びBash入門/次世代シークエンス解析入門

    2021

  3. 基盤医科学実習 CIBoG Linux及びBash入門/次世代シークエンス解析入門

    2020