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Anti-tumor approach based on the understanding of NFAT-EC activation system

Research Project

Project/Area Number 17H03580
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionKumamoto University

Principal Investigator

Minami Takashi  熊本大学, 生命資源研究・支援センター, 教授 (00345141)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Keywords血管内皮細胞 / 血管新生 / NFAT / ダウン症因子 / EndMT / 転写因子 ERG / 転写因子 FLI1 / がん微小環境 / ダウン症モデル / 担がんモデル / Notch シグナル / 血管分岐 / マイクロアレイ / 腫瘍血管新生 / ダウン症病態 / NFAT/DSCR-1 シグナル / 内皮エピゲノム病態 / 内皮ー間葉系形質転換 / Erg / FLI1 / 内皮エピゲノム制御 / 内皮多様性 / Notch / 腫瘍血管 / ChIP-seq / エピゲノム制御 / エクササイズ / NFAT/DSCR-1
Outline of Final Research Achievements

Endothelial cell (EC) plasticity in pathological settings has been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here we found, combined knockdown of ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG/FLI1 are critical transcriptional activators for EC-specific genes, among which miR-126 partially contributes to blocking the EndMT induction. Moreover, we demonstrated that ERG and FLI1 expression is declined in ECs within tumor by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in EC, and its behavior in pathological condition.

Academic Significance and Societal Importance of the Research Achievements

内皮活性化に関わる NFAT/DSCR-1経路において、DSCR-1はダウン症の発症要因となる一方、DSCR-1 自体のトリソミー発現がダウン症の固形がん罹患率減少の主因となり、抗がんや抗転移における優れた有効性を持つ。また、がんの悪性化、転移において腫瘍血管内皮の EndMT 現象が関与することが考えられ、その分子メカニズムの一端が解明されたことにより、今後抗がんにおける腫瘍血管の動態解析の重要性が再認識され、新規な DSCR-1 安定化剤の創薬や臨床アプローチが進むことが期待される。

Report

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

    (27 results)

All 2019 2018 2017 Other

All Int'l Joint Research (6 results) Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 6 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (10 results) (of which Int'l Joint Research: 7 results,  Invited: 6 results) Remarks (4 results)

  • [Int'l Joint Research] Harvard Medical School/MD Anderson Cancer Center/NorthWestern University(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Harvard Medical School/U.Penn/NorthWestern University(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] KAIST(韓国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] U.Penn/MD Anderson Cancer Center/Harvard Medical School(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] CNIC(Spain)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Seoul National University/KAIST(韓国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Organ/Tissue-Specific Vascular Endothelial Cell Heterogeneity in Health and Disease2019

    • Author(s)
      Minami Takashi、Muramatsu Masashi、Kume Tsutomu
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 10 Pages: 1609-1619

    • DOI

      10.1248/bpb.b19-00531

    • NAID

      130007722463

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-10-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice2019

    • Author(s)
      Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
    • Journal Title

      Circulation Journal

      Volume: 83 Issue: 2 Pages: 368-378

    • DOI

      10.1253/circj.CJ-18-0925

    • NAID

      130007557092

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2019-01-25
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 血管形成・血管新生を担う転写因子ネットワーク──内皮エピゲノム環境に基づく転写カスケード2019

    • Author(s)
      南 敬
    • Journal Title

      医学のあゆみ 血管新生

      Volume: 270 Pages: 51-56

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition2018

    • Author(s)
      Nagai Nao、Ohguchi Hiroto、Nakaki Ryo、Matsumura Yoshihiro、Kanki Yasuharu、Sakai Juro、Aburatani Hiroyuki、Minami Takashi
    • Journal Title

      PLOS Genetics

      Volume: 14 Issue: 11 Pages: e1007826-e1007826

    • DOI

      10.1371/journal.pgen.1007826

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation2018

    • Author(s)
      3.Baba M, Endoh M, Ma W, Toyama H, Hirayama A, Nishikawa K, Takubo K, Hano H, Hasumi H, Umemoto T, Hashimoto M, Irie N, Esumi C, Kataoka M, Nakagata N, Soga T, Yao M, Kamba T, Minami T, Ishii M, and Suda T.
    • Journal Title

      Journal of Bone and Mineral Research

      Volume: 33 Issue: 10 Pages: 1785-1798

    • DOI

      10.1002/jbmr.3477

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription is indispensable for endothelial cell differentiation2017

    • Author(s)
      Kanki Y, Nakaki R, Shimamura T, Matsunaga T, Yamamizu K, Katayama S, Suehiro JI, Osawa T, Aburatani H, Kodama T, Wada Y, Yamashita JK, Minami T.
    • Journal Title

      Nucleic Acids Research

      Volume: 印刷中 Issue: 8 Pages: 4344-4358

    • DOI

      10.1093/nar/gkx159

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1.2017

    • Author(s)
      Nakamura S, Koyama T, Izawa N, Nomura S, Fujita T, Omata Y, Minami T, Matsumoto M, Nakamura M, Fujita-Jimbo E, Momoi T, Miyamoto T, Aburatani H, Tanaka S.
    • Journal Title

      PLoS One

      Volume: 12 Issue: 4 Pages: e0175632-e0175632

    • DOI

      10.1371/journal.pone.0175632

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Uncovering VEGF-stimulated variable epigenome landscape in endothelium2019

    • Author(s)
      Minami, T
    • Organizer
      Gordon Research Conference 2019 Epigenetic Regulation of Cardiovascular Disease(国際学会)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Homeostasis in NFAT1-Down syndrome critical region-1 signaling is critical for regulation of proper vessel formation and vascular integrity2019

    • Author(s)
      Muramatsu M., Ryeom S., Uemura A., and Minami T.
    • Organizer
      第3回Asia Australia Vascular Biology Meeting(AAVBM)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Homeostasis in NFAT-DSCR-1 signaling is critical for initial epigenetic conversion and the following proper vessel formation2019

    • Author(s)
      Minami, T
    • Organizer
      NIH Vascular Annual Seminar series
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Epigenetic modifier regulates accurate transcription on the bivalent histone marked angiogenic genes in endothelium2019

    • Author(s)
      Yasuharu Kanki, Yuri Miyamura, Masashi Muramatsu, and Takashi Minami
    • Organizer
      Cell Sympojium_2019_Epigenetics
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] VEGF 刺激によるヒストンダイナミクスを介した内皮分化 及び血管分岐応答制御機構の解明2019

    • Author(s)
      南 敬
    • Organizer
      CVMW2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A novel endothelial cell specific-gene, DESM, regulated pathological angiogenesis2019

    • Author(s)
      Yuri Miyamura, Masashi Muramatsu, Takashi Minami
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Homeostasis in NFAT-Down syndrome critical region-1 signaling is critical for regulation of proper vessel formation and vascular integrity.2017

    • Author(s)
      Minami T
    • Organizer
      Ts21 International conference 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Endothelial cell heterogeneity2017

    • Author(s)
      Minami T
    • Organizer
      Korea-Japan Joint symposium for Vascular Medicine
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ダウン症因子 DSCR-1 による 血管恒常性制御と加齢病態2017

    • Author(s)
      南 敬
    • Organizer
      Con Bio 2017
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] NFAT/ダウン症因子 (DSCR-1) シグナルに基づく 内皮活性化と病的血管新生制御2017

    • Author(s)
      南 敬
    • Organizer
      日本薬学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Remarks] 2020.2.4-5 文科省先端モデル動物支援成果発表会に参加しました

    • URL

      http://irda-vascular.kuma-u.jp/news/2020/02/202024-5.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 血管分化を導く遺伝プログラムの一部を解明 ―血管分化におけるヒストンと転写のはたらきを同定―

    • URL

      http://irda-vascular.kuma-u.jp/news/2017/03/es-nucleicacidsresearch.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] ES 細胞から内皮分化におけるゲノムワイドな解析を報告しました

    • URL

      http://irda-vascular.kuma-u.jp/news/2017/03/es-nucleicacidsresearch.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 血管分化を導く遺伝プログラムの一部を解明 ―血管分化におけるヒストンと転写のはたらきを同定―

    • URL

      http://irda-vascular.kuma-u.jp/news/2017/03/es-nucleicacidsresearch.html

    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2022-07-19  

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