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Generation and maintenance mechanism of cancer stem cells in tumor microenvironment, involved in lung cancer development and reocurrence.

Research Project

Project/Area Number 17H04054
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionNippon Medical School

Principal Investigator

Tanaka Nobuyuki  日本医科大学, 大学院医学研究科, 大学院教授 (80222115)

Co-Investigator(Kenkyū-buntansha) 清水 幹容  日本医科大学, 大学院医学研究科, ポストドクター (00774358)
弦間 昭彦  日本医科大学, 大学院医学研究科, 大学院教授 (20234651)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Keywordsがん幹細胞 / がん治療 / IL-8 / O-GlcNAcylation / GLI1 / MEP50 / PRMT5 / 薬剤スクリーニング / p53 / リプログラミング / SOX2 / OCT4 / 肺がん / がん微小環境 / がんの再発防止 / STAT3 / O-GlcNAc修飾 / グルコース代謝 / がんの再発 / がん化学療法 / Sox2
Outline of Final Research Achievements

Cancer stem cells (CSCs) are a subset of tumor cells that exhibit self-renewal ability and generate the diverse cells that comprise the tumor. CSCs show increased quiescence and poor responses to conventional chemotherapy. We found that IL-8 is overexpressed in lung cancer stem cells and is required for CSC properties, including tumor-initiating abilities. IL-8 stimulation of lung cancer cells induced glucose uptake, resulting in enhancement of protein O-GlcNAcylation, and these events were required for the generation and maintenance lung CSCs. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of lung cancer cells. Moreover, we also found novel activation mechanism of transcription factor GLI1, critical regulator of stem cells, by the methylosome MEP50/PRMT5 complex in lung cancer cells.

Academic Significance and Societal Importance of the Research Achievements

我々の研究から、炎症性ケモカインIL-8によるタンパクのO-GlcNAc修飾の増加が肺がんのがん幹細胞の発生と維持に重要であること、この機構ががん幹細胞の治療の有用な標的となることを見出した。また、がん幹細胞の発生と維持に重要でな転写因子GLI1のMEP50/PRMT5を介した新しい活性化機構を発見し、この機構が肺がんでも働いていることを見出した。この機構もがんの治療の標的として有効であると考えられ、現在GLI1とMEP50との結合を阻害する薬剤のスクリーニングを試みている。これらのことは、がん幹細胞の発生機構の解明と新たな肺がんの治療法の開発につながり、学術的・社会的意義が高いと考えている。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (34 results)

All 2020 2019 2018 2017

All Journal Article (8 results) (of which Peer Reviewed: 8 results,  Open Access: 4 results) Presentation (26 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] MMP24 as a Target of YAP Is a Potential Prognostic Factor in Cancer Patients2020

    • Author(s)
      Wataru Sugimoto、Katsuhiko Itoh、Hiroaki Hirata、Yoshinori Abe、Takeru Torii、Yasumasa Mitsui、Yemima Budirahardja、Nobuyuki Tanaka、Keiko Kawauchi
    • Journal Title

      Bioengineering

      Volume: 7 Issue: 1 Pages: 18-18

    • DOI

      10.3390/bioengineering7010018

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cochlear supporting cells function as macrophage-like cells and protect audiosensory receptor hair cells from pathogens2020

    • Author(s)
      Yushi Hayashi, Hidenori Suzuki, Wataru Nakajima, Ikuno Uehara, Atsuko Tanimura, Toshiki Himeda, Satoshi Koike, Tatsuya Katsuno, Shin-ichiro Kitajiri, Naoto Koyanagi, Yasushi Kawaguchi, Koji Onomoto, Hiroki Kato, Mitsutoshi Yoneyama, Takashi Fujita, Nobuyuki Tanaka
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 6740-6740

    • DOI

      10.1038/s41598-020-63654-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death2019

    • Author(s)
      Itoh Katsuhiko、Ebata Takahiro、Hirata Hiroaki、Torii Takeru、Sugimoto Wataru、Onodera Keigo、Nakajima Wataru、Uehara Ikuno、Okuzaki Daisuke、Yamauchi Shota、Budirahardja Yemima、Nishikata Takahito、Tanaka Nobuyuki、Kawauchi Keiko
    • Journal Title

      Molecules

      Volume: 24 Issue: 17 Pages: 3175-3175

    • DOI

      10.3390/molecules24173175

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MEP50/PRMT5-mediated methylation activates GLI1 in Hedgehog signalling through inhibition of ubiquitination by the ITCH/NUMB complex2019

    • Author(s)
      Abe Yoshinori、Suzuki Yosuke、Kawamura Kenji、Tanaka Nobuyuki
    • Journal Title

      Communications Biology

      Volume: 2 Issue: 1 Pages: 1-10

    • DOI

      10.1038/s42003-018-0275-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells2018

    • Author(s)
      Shimizu Masahiro、Tanaka Nobuyuki
    • Journal Title

      Oncogene

      Volume: 38 Issue: 9 Pages: 1520-1533

    • DOI

      10.1038/s41388-018-0533-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of p53 in the Regulation of the Inflammatory Tumor Microenvironment and Tumor Suppression2018

    • Author(s)
      Uehara Ikuno、Tanaka Nobuyuki
    • Journal Title

      Cancers

      Volume: 10 Issue: 7 Pages: 219-219

    • DOI

      10.3390/cancers10070219

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chaperone-mediated autophagy promotes lung cancer cell survival through selective stabilization of the pro-survival protein, MCL12017

    • Author(s)
      Junya Suzuki, Wataru Nakajima, Hidenori Suzuki, Yumi Asano, Nobuyuki Tanaka
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 482 Issue: 4 Pages: 1334-1340

    • DOI

      10.1016/j.bbrc.2016.12.037

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer2017

    • Author(s)
      Abe Yoshinori、Tanaka Nobuyuki
    • Journal Title

      Journal of Developmental Biology

      Volume: 5 Issue: 4 Pages: 12-12

    • DOI

      10.3390/jdb5040012

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Role of MEP50/PRMT5 complex in hedgehog signaling pathway-activated cancer cells2019

    • Author(s)
      Yoshinori Abe, Nobuyuki Tanaka
    • Organizer
      第78回 日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Analysis of molecular mechanism by HIF-1a in gefitinib-resistance acquisition in lung cancer2019

    • Author(s)
      Chisato Iwabuchi, Nobuyuki Tanaka
    • Organizer
      第78回 日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 2-Deoxy-d-glucose is a candidate therapeutic agent for inflammation-induced cancer2019

    • Author(s)
      Ikuno Uehara, Nobuyuki Tanaka
    • Organizer
      第78回 日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Analysis of microtubule-targeting agents-induced apoptosis in triple-negative breast cancer2019

    • Author(s)
      Wataru Nakajima, Tomoko Kurita, Masahiro Sakaguchi, Takashi Sakatani, Zenma Naito, Hiroyuki Takei, Nobuyuki Tanaka
    • Organizer
      第78回 日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 恒常的にhedgehogシグナル伝達経路が活性化した癌細胞におけるMEP50/PRMT5複合体の役割2019

    • Author(s)
      阿部 芳憲, 田中 信之
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] MYD88シグナルの恒常的活性化はNF-kB/HIF-1aを介して癌化を促進する2019

    • Author(s)
      谷村 篤子, 中里 茜, 田中 信之
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] cGAS-STING経路を介して産生されるI型インターフェロンのがん細胞における役割2019

    • Author(s)
      上原 郁野, 梶田 満子, 田中 信之
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] IL-8はGLUT3とGFATを介してO-GlcNAc修飾を誘導し、癌幹細胞能を制御する2019

    • Author(s)
      清水 幹容, 田中 信之
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] トリプルネガティブ乳がんにおける化学療法抵抗性分子機構の解析2019

    • Author(s)
      中嶋 亘 , 浅野 由ミ, 田中 信之
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アポトーシス を誘導するp73の新規標的分子の同定2019

    • Author(s)
      取井 猛流, 伊藤 功彦, 江畑 貴弘, 平田 宏聡, 杉本 渉, 小野寺 恵吾, 中嶋 亘, 上原 郁野, 奥崎 大介, 山内 翔太, Yemima Budirahardja, 西方 敬人, 田中 信之, 川内 敬子
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] PRMT5 Mediated Gli1 Activation Pathway Maintains Cancer Stem Cells in Non-Small Cell Lung Cancer.2018

    • Author(s)
      Yoshinori Abe, Susumu Takeuchi, Masahiko Seike, Akihiko Gemma, Nobuyuki Tanaka
    • Organizer
      The 6th JCA-AACR Special Joint Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analysis of Paclitaxel-induced apoptosis in triple-negative breast cancer.2018

    • Author(s)
      中嶋 亘、栗田 智子、浅野 由ミ、武井 寛幸、田中 信之
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] MyD88-activated form induces oncogenesis via NFκB - HIF1α2018

    • Author(s)
      谷村篤子、田中信之
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Effect of Type I interferon in cancer stem cell maintenance and tumorigenesis.2018

    • Author(s)
      上原郁野、田中信之
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] CRISPR/CAS9システムによるGLI1ノックアウト肺腺癌細胞の解析2018

    • Author(s)
      阿部芳憲、田中信之
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Analysis of the involvement of BRCA1 and Mcl-1 in Paclitaxel-induced apoptosis of triple-negative breast cancer cells.2018

    • Author(s)
      中嶋 亘 、栗田 智子 、武井 寛幸 、田中 信之
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アルギニンメチル基転移酵素PRMT5の大腸癌における役割2018

    • Author(s)
      阿部芳憲、枝川聖子、谷村篤子、上原郁野、田中信之
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] MyD88-activated form induces oncogenesis via NFκB-HIF1α2018

    • Author(s)
      谷村篤子、中里茜、田中信之
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Analysis of molecular mechanism by HIF-1α in gefitinib-resistance acquisitiuon in lung cancer2018

    • Author(s)
      岩渕千里, 田中信之
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The molecular mechanism of PRMT5-mediated colon cancer development.2017

    • Author(s)
      阿部芳憲、田中信之
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] The analysis of CRISPR/Cas9-mediated GLI1 knockout lung adenocarcinoma cells.2017

    • Author(s)
      阿部芳憲、田中信之
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Analysis of Paclitaxel-induced apoptosis in triple-negative breast cancer.2017

    • Author(s)
      中嶋 亘、浅野由ミ、武井寛幸、田中信之
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Effect of type I interferon in cancer stem cell and tumorigenesis.2017

    • Author(s)
      上原郁野、田中信之
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] MyD88-activated form induces oncogenesis via NFκB-HIF1α2017

    • Author(s)
      谷村篤子、中里茜、田中信之
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] IL-8 supports development of cancer stem cells via glucose metabolism.2017

    • Author(s)
      清水 幹容、田中 信之
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Cisplatin-induced apoptosis in non-small cell lung cancer cells.2017

    • Author(s)
      中道真仁、中嶋 亘、田中信之
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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