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Integrative functional analysis of G-quadruplex nucleic acids by utilizing natural and synthetic chemical tool molecules

Publicly Offered Research

Project AreaFrontier research of chemical communications
Project/Area Number 18H04633
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

清宮 啓之  公益財団法人がん研究会, がん化学療法センター 分子生物治療研究部, 部長 (50280623)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywordsグアニン4重鎖 / テロメア / 天然化合物 / バイオプローブ / オミクス解析 / 化学シグナル / グアニン4重鎖 / グアニン四重鎖 / ケミカルツール分子
Outline of Annual Research Achievements

放線菌Streptomyces anulatus由来の強力なG4安定化物質(G4リガンド)であるテロメスタチンおよびその合成誘導体、ならびにこれらと母核構造の異なるG4リガンドPhen-DC3を処理したヒト細胞について、G4および核内DNA損傷フォーカスの定量解析、GeneChipマイクロアレイによる網羅的遺伝子発現解析および変動パスウェイ解析を実施し、G4の安定化に伴う細胞内応答パターンを包括的に捉えた多層データベースを拡充した。網羅的遺伝子発現解析では、多くのリガンドおよび細胞に共通してミトコンドリアゲノム由来遺伝子群への影響が検出された。ミトコンドリアゲノムにはG4形成配列が豊富に存在し、同ゲノム由来遺伝子の発現変動はG4リガンドの選択的な薬力学効果を示すバイオマーカーとなる可能性が示唆された。なお、G4リガンドを処理した細胞において、ミトコンドリアの形態および機能に顕著な変化は認められなかった。一方、G4リガンドの増殖阻害効果が顕著に現れた膵がん細胞株に着目し、G4リガンド処理によって発現変動するタンパク質を網羅同定した。発現低下したタンパク質をコードする遺伝子のセンス鎖には、G4形成配列が有意に多く含まれていた。このことから、転写されたRNA上のG4がリガンドで安定化され、翻訳の障害となる可能性が示唆された。また、本領域A03班の「化学シグナルの統合解析法」に関する成果として、JFCR_LinCAGE遺伝子発現データベースなどの化合物プロファイリング技術を活用し、患者由来胃がん細胞のCD44陽性がん幹細胞画分の生存因子として上皮増殖因子受容体(EGFR)を同定することに成功した。さらにシングルセルRNA解析により、患者由来胃がん細胞の生存因子としてアルデヒド脱水素酵素ALDH1A3を同定した。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (52 results)

All 2020 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (17 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 17 results,  Open Access: 10 results) Presentation (25 results) (of which Int'l Joint Research: 6 results,  Invited: 16 results) Book (2 results) Remarks (2 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results) Funded Workshop (1 results)

  • [Int'l Joint Research] Universite Claude Bernard Lyon1(フランス)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] アラバマ大学バーミングハム校(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] G-quadruplex in cancer biology and drug discovery.2020

    • Author(s)
      Nakanishi C, Seimiya H.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: In press Issue: 1 Pages: 45-50

    • DOI

      10.1016/j.bbrc.2020.03.178

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer.2020

    • Author(s)
      Shirai F, Mizutani A, Yashiroda Y, Tsumura T, Kano Y, Muramatsu Y, Chikada T, Yuki H, Niwa H, Sato S, Washizuka K, Koda Y, Mazaki Y, Jang MK, Yoshida H, Nagamori A, Okue M, Watanabe T, Kitamura K, Shitara E, Honma T, Umehara T, et al.
    • Journal Title

      J Med Chem

      Volume: 63 Issue: 8 Pages: 4183-4204

    • DOI

      10.1021/acs.jmedchem.0c00045

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ALDH1A3-mTOR axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer.2020

    • Author(s)
      Kawakami R, Mashima T, Kawata N, Kumagai K, Migita T, Sano T, Mizunuma N, Yamaguchi K, Seimiya H
    • Journal Title

      Cancer Sci

      Volume: 111 Issue: 3 Pages: 962-973

    • DOI

      10.1111/cas.14316

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tankyrase Inhibitors Target Colorectal Cancer Stem Cells via AXIN-Dependent Downregulation of c-KIT Tyrosine Kinase.2020

    • Author(s)
      Jang MK, Mashima T, Seimiya H
    • Journal Title

      Mol Cancer Ther

      Volume: 19 Issue: 3 Pages: 765-776

    • DOI

      10.1158/1535-7163.mct-19-0668

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib2020

    • Author(s)
      Matsusaka Satoshi、Hanna Diana L.、Ning Yan、Yang Dongyun、Cao Shu、Berger Martin D.、Miyamoto Yuji、Suenaga Mitsukuni、Dan Shingo、Mashima Tetsuo、Seimiya Hiroyuki、Zhang Wu、Lenz Heinz‐Josef
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 2 Pages: 441-450

    • DOI

      10.1111/cas.14273

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tankyrase promotes primary precursor miRNA processing to precursor miRNA.2020

    • Author(s)
      Mizutani A, Seimiya H.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 52 Issue: 4 Pages: 945-951

    • DOI

      10.1016/j.bbrc.2019.11.191

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] From the wings to the center stage of chromosomes.2019

    • Author(s)
      Okamoto K, Seimiya H.
    • Journal Title

      J Biol Chem

      Volume: 294 Issue: 47 Pages: 17723-17724

    • DOI

      10.1074/jbc.h119.011587

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] In silico chemical screening identifies epidermal growth factor receptor as a therapeutic target of drug-tolerant CD44v9-positive gastric cancer cells.2019

    • Author(s)
      Mashima T, Iwasaki R, Kawata N, Kawakami R, Kumagai K, Migita T, Sano T, Yamaguchi K, Seimiya H
    • Journal Title

      Br J Cancer

      Volume: 121 Issue: 10 Pages: 846-856

    • DOI

      10.1038/s41416-019-0600-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors.2019

    • Author(s)
      Shirai F, Tsumura T, Yashiroda Y, Yuki H, Niwa H, Sato S, Chikada T, Koda Y, Washizuka K, Yoshimoto N, Abe M, Onuki T, Mazaki Y, Hirama C, Fukami T, Watanabe H, Honma T, Umehara T, Shirouzu M, Mizutani A, et al.
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 62 Issue: 7 Pages: 3407-3427

    • DOI

      10.1021/acs.jmedchem.8b01888

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Meeting report of the 14th Japan Korea joint symposium on cancer and aging research: current status of translational research and approaches to precision medicine2019

    • Author(s)
      Sueoka Eisaburo、Watanabe Tatsuro、Mashima Tetsuo、Shirakami Yohei、Komori Atsumasa、Matsuo Keitaro、Yoshikawa Hiroshi Y.、Cho Kyung A、Park Tae Jun、Seimiya Hiroyuki、Kim Eung-Gook、Suganuma Masami、Chung Junho
    • Journal Title

      Journal of Cancer Research and Clinical Oncology

      Volume: 印刷中 Issue: 5 Pages: 1263-1271

    • DOI

      10.1007/s00432-019-02887-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study2019

    • Author(s)
      Suenaga Mitsukuni、Wakatsuki Takeru、Mashima Tetsuo、Ogura Mariko、Ichimura Takashi、Shinozaki Eiji、Nakayama Izuma、Osumi Hiroki、Ota Yumiko、Takahari Daisuke、Chin Keisho、Seimiya Hiroyuki、Yamaguchi Kensei
    • Journal Title

      Investigational New Drugs

      Volume: 印刷中 Issue: 1 Pages: 2567-2575

    • DOI

      10.1007/s10637-019-00749-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Revisiting Telomere Shortening in Cancer.2019

    • Author(s)
      Keiji Okamoto and Hiroyuki Seimiya
    • Journal Title

      Cells

      Volume: 8 Issue: 2 Pages: 107-107

    • DOI

      10.3390/cells8020107

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells2018

    • Author(s)
      Fujiwara C, Muramatsu Y, Nishii M, Tokunaka K, Tahara H, Ueno M, Yamori T, Sugimoto Y, Seimiya H8
    • Journal Title

      Sci Rep.

      Volume: 8 Issue: 1 Pages: 1-15

    • DOI

      10.1038/s41598-018-33139-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of G-quadruplex ligands for selective induction of a parallel-type topology2018

    • Author(s)
      Ma Yue、Tsushima Yamato、Sakuma Mai、Sasaki Shogo、Iida Keisuke、Okabe Sachiko、Seimiya Hiroyuki、Hirokawa Takatsugu、Nagasawa Kazuo
    • Journal Title

      Organic & Biomolecular Chemistry

      Volume: 16 Issue: 40 Pages: 7375-7382

    • DOI

      10.1039/c8ob01702f

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B2018

    • Author(s)
      Hatta Tomohisa、Iemura Shun-ichiro、Ohishi Tomokazu、Nakayama Hiroshi、Seimiya Hiroyuki、Yasuda Takao、Iizuka Katsumi、Fukuda Mitsunori、Takeda Jun、Natsume Tohru、Horikawa Yukio
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 16756-16756

    • DOI

      10.1038/s41598-018-35204-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs.2018

    • Author(s)
      Keiji Okamoto, Tomokazu Ohishi, Mika Kuroiwa, Shun-ichiro Iemura, Tohru Natsume and Hiroyuki Seimiya
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 88 Pages: 35844-35855

    • DOI

      10.18632/oncotarget.26312

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model.2018

    • Author(s)
      Mizutani A, Yashiroda Y, Muramatsu Y, Yoshisa H, Chikada T, Tsumura T, Okue M, Shirai F, Fukami T, Yoshida M, Seimiya H.
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 12 Pages: 4003-4014

    • DOI

      10.1111/cas.13805

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Telomere as the starting point of anticancer drug discovery2020

    • Author(s)
      Seimiya H.
    • Organizer
      LyonSE&N - ELyT Workshop 2020
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 腫瘍形成におけるインターフェロン標的遺伝子ISG15の機能解明2020

    • Author(s)
      犬山慶輔、 岡本啓治、右田敏郎、藤原理恵、清宮啓之
    • Organizer
      文部科学省新学術領域研究 学術研究支援基盤形成 先端モデル動物支援プラットフォーム 2019年度成果発表会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Tankyrase and G-quadruplex as molecular targets for cancer therapy2019

    • Author(s)
      Seimiya H.
    • Organizer
      第25回日本遺伝子細胞治療学会シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Telomere as the starting point of anticancer drug discovery2019

    • Author(s)
      Seimiya H.
    • Organizer
      The 7th Symposium, RIKEN-Max Planck Joint Research Center
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 四重鎖核酸ケモプローブに対する細胞応答の解明とがん創薬への応用2019

    • Author(s)
      清宮啓之
    • Organizer
      第92回日本生化学会大会シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Crossroads of telomere biology and cancer drug discovery2019

    • Author(s)
      Seimiya H.
    • Organizer
      第78回日本癌学会学術総会コアシンポジウム
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ケミカルツールを利用した四重鎖核酸の統合機能解析とその応用2019

    • Author(s)
      清宮啓之
    • Organizer
      化学コミュニケーションのフロンティア第6回公開シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] テロメアから始まるがん創薬2019

    • Author(s)
      清宮啓之
    • Organizer
      JSPS「日本におけるケミカルバイオロジーの新展開」 に関する産学協力研究委員会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] がんにおけるテロメア短縮のパラドクスを再考する2019

    • Author(s)
      岡本啓治、清宮啓之
    • Organizer
      第42回日本分子生物学会年会ワークショップ
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 分子プロファイリング支援活動のご紹介 ~小さな分子を起点とした生命科学研究のお手伝い2019

    • Author(s)
      清宮啓之
    • Organizer
      文部科学省新学術領域研究 学術研究支援基盤形成 先端モデル動物支援プラットフォーム 2019年度若手支援技術講習会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] テロメア非コードRNAとがん2019

    • Author(s)
      清宮啓之
    • Organizer
      JARIランチョンセミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Wnt/G4を標的としたがん創薬2019

    • Author(s)
      清宮啓之
    • Organizer
      広島大学大学院医系科学研究科セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 染色体の末端から始まるがん創薬2019

    • Author(s)
      清宮啓之
    • Organizer
      徳島大学大学院医歯薬学研究部 呼吸器・膠原病内科学分野 開講48周年記念会 篠原 勉先生 特任教授就任祝賀会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 制がん性グアニン四重鎖リガンドの新たな作用機序の解明2019

    • Author(s)
      岡部幸子、岡本啓治、新家一男、旦 慎吾、長澤和夫、清宮啓之
    • Organizer
      第23回日本がん分子標的治療学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] テロメア長による遺伝子発現制御と腫瘍形態への影響2019

    • Author(s)
      岡本啓治、清宮啓之
    • Organizer
      第23回日本がん分子標的治療学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] プロテオーム解析による制がん性グアニン四重鎖リガンドの標的分子の探索2019

    • Author(s)
      中西忠也、岡部幸子、岡本啓治、小林美月、新家一男、長澤和夫、清宮啓之
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] グアニン四重鎖リガンドによるミトコンドリア遺伝子の発現制御2019

    • Author(s)
      岡部幸子、井上直、村松由起子、新家一男、長澤和夫、清宮啓之
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 天然・合成ケミカルツール分子を利用した四重鎖核酸の統合機能解析2019

    • Author(s)
      岡部幸子、岡本啓治、新家一男、旦慎吾、長澤和夫、清宮啓之
    • Organizer
      化学コミュニケーションのフロンティア第5回公開シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] グアニン四重鎖リガンドによるがん細胞選択的なタンパク質翻訳阻害2019

    • Author(s)
      中西忠也、岡部幸子、岡本啓治、小林美月、 新家一男、長澤和夫、清宮啓之
    • Organizer
      化学コミュニケーションのフロンティア第5回公開シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] Telomere as the starting point of anticancer drug discovery2019

    • Author(s)
      Hiroyuki Seimiya
    • Organizer
      11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] グアニン4重鎖安定化物質の分子プロファイリングとがん創薬への展開2019

    • Author(s)
      清宮啓之、新家一男、長澤和夫
    • Organizer
      日本農芸化学会2019年度大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Targeting glioma stem cells by pharmacological stabilization of G-quadruplexes2018

    • Author(s)
      Sachiko Okabe, Takahiro Nakamura, Daiki Hasegawa, Reina Kojima, Keiji Okamoto, Ichiro Nakano, Kazuo Shin-ya, Kazuo Nagasawa, Hiroyuki Seimiya
    • Organizer
      AACR Annual Meeting 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] G-quadruplex nucleic acids as a molecular target for cancer therapy2018

    • Author(s)
      Hiroyuki Seimiya, Kazuo Shin-ya, Kazuo Nagasawa
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] New mode-of-action of a telomerase inhibitor MST-312 and modifiers of its anticancer efficacy2018

    • Author(s)
      藤原千明、村松由起子、矢守隆夫、杉本芳一、清宮啓之
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] G-quadruplex as a molecular target for cancer therapy2018

    • Author(s)
      Hiroyuki Seimiya
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Book] 進化するがん創薬2019

    • Author(s)
      清宮啓之(編)
    • Total Pages
      344
    • Publisher
      化学同人
    • ISBN
      4759817336
    • Related Report
      2019 Annual Research Report
  • [Book] 決定版 阻害剤・活性化剤ハンドブック:テロメラーゼ関連薬剤2019

    • Author(s)
      新家一男、清宮啓之(秋山徹、河府和義 編)
    • Total Pages
      648
    • Publisher
      羊土社
    • ISBN
      9784758120999
    • Related Report
      2019 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      https://www.jfcr.or.jp/chemotherapy/department/molecular_biotherapy/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      https://www.jfcr.or.jp/chemotherapy/department/molecular_biotherapy/index.html

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] がんを治療するための組み合わせ物及び医薬組成物2020

    • Inventor(s)
      長澤和夫、松田未沙子、馬悦、清宮啓之
    • Industrial Property Rights Holder
      国立大学法人東京農工大学、公益財団法人がん研究会
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-008592
    • Filing Date
      2020
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗がん剤2019

    • Inventor(s)
      長澤和夫、松田未沙子、馬悦、清宮啓之
    • Industrial Property Rights Holder
      国立大学法人東京農工大学、公益財団法人がん研究会
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 抗膵がん剤2018

    • Inventor(s)
      長澤和夫、松田未沙子、馬悦、清宮啓之
    • Industrial Property Rights Holder
      東京農工大学、がん研究会
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
  • [Funded Workshop] The 14th Japan-Korea Joint Symposium on Cancer and Ageing Research2018

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2021-01-27  

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