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Analysis of cancer-promoting mechanism of estrogen-responsive genes and its application to molecular target in female cancers

Research Project

Project/Area Number 16K09809
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Endocrinology
Research InstitutionSaitama Medical University

Principal Investigator

Sato Wataru  埼玉医科大学, 医学部, 助手 (10772783)

Co-Investigator(Kenkyū-buntansha) 池田 和博  埼玉医科大学, 医学部, 講師 (30343461)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsステロイドホルモン / 遺伝子発現 / がん / 腫瘍免疫 / エストロゲン / 治療薬耐性 / 女性がん / 乳がん / 子宮体がん
Outline of Final Research Achievements

Estrogen, a female hormone, is involved in development and progression of cancer in women; however, the precise mechanism is still unknown. In this study, we revealed that the estrogen-responsive gene Efp promotes growth and migration of hormone-independent and therapeutic drug-resistant endometrial cancer cells through activating intracellular inflammation signal. In addition, the other estrogen-responsive gene EBAG9 is shown to be secreted from cancer cells as exosomes (small extracellular vesicles). The exosome-mediated EBAG9 transfer stimulated migration of cancer cells while inhibited cytotoxicity of immune T-cells, indicating a role in immune checkpoint regulation. These findings may provide novel molecular targets for cancer therapy.

Academic Significance and Societal Importance of the Research Achievements

がんにおいて治療抵抗性の獲得は臨床上大きな問題であるが、抵抗性獲得のメカニズムは未だ解明されておらず、効果的な対処法に乏しい。本研究は、子宮体がんをはじめとする女性のがんにおいて、エストロゲン応答遺伝子の機能解明からこの問題の解決策を探る特色がある。Efpが制御する新しい細胞内シグナル経路の同定、ならびにEBAG9がエクソソームを介して腫瘍免疫に作用することを明らかにしている知見等は、学術的に新しく、内分泌学とその関連領域の発展に資すると考えられる。免疫チェックポイント機構を標的としたがん治療薬は、最近最も注目されている分野の1つであり社会的な意義が大きいと考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (22 results)

All 2019 2018 2017 2016

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 5 results) Presentation (15 results) (of which Int'l Joint Research: 3 results) Book (1 results)

  • [Journal Article] Efp promotes in vitro and in vivo growth of endometrial cancer cells along with the activation of nuclear factor-κB signaling2018

    • Author(s)
      Sato Wataru、Ikeda Kazuhiro、Urano Tomohiko、Abe Yayoi、Nakasato Norie、Horie-Inoue Kuniko、Takeda Satoru、Inoue Satoshi
    • Journal Title

      PLOS ONE

      Volume: 13 Issue: 12 Pages: 0208351-0208351

    • DOI

      10.1371/journal.pone.0208351

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression2018

    • Author(s)
      Miyazaki Toshiaki、Ikeda Kazuhiro、Sato Wataru、Horie-Inoue Kuniko、Inoue Satoshi
    • Journal Title

      Oncogenesis

      Volume: 7 Issue: 1 Pages: 7-7

    • DOI

      10.1038/s41389-017-0022-6

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer2018

    • Author(s)
      Takayama Ken-ichi、Suzuki Takashi、Tanaka Tomoaki、Fujimura Tetsuya、Takahashi Satoru、Urano Tomohiko、Ikeda Kazuhiro、Inoue Satoshi
    • Journal Title

      Oncogene

      Volume: 37 Issue: 16 Pages: 2165-2180

    • DOI

      10.1038/s41388-017-0095-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Estrogen signaling increases nuclear receptor subfamily 4 group A member 1 expression and energy production in skeletal muscle cells2018

    • Author(s)
      Nagai S, Ikeda K, Horie-Inoue K, Takeda S, Inoue S
    • Journal Title

      Endocrine Journal

      Volume: 65 Issue: 12 Pages: 1209-1218

    • DOI

      10.1507/endocrj.EJ17-0548

    • NAID

      130007553312

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Proteasome 26S subunit PSMD1 regulates breast cancer cell growth through p53 protein degradation2018

    • Author(s)
      Okumura T,Ikeda K,Sato W,Horie-Inoue K,Takeda S,Inoue S
    • Journal Title

      J Biochem

      Volume: 163 Issue: 1 Pages: 19

    • DOI

      10.1093/jb/mvx053

    • NAID

      40021457346

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Estrogen modulates exercise endurance along with mitochondrial uncoupling protein3 downregulation in skeletal muscle of females mice2016

    • Author(s)
      Nagai S, Ikeda K, Horie-Inoue K, Shiba S, Nagasawa S, Takeda S, Inoue S
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 4 Pages: 758-764

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Oncogenic roles of tripartite motif 25 in endometrial cancer2019

    • Author(s)
      Horie-Inoue K, Satou W, Ikeda K, Inoue s
    • Organizer
      ENDO2019, New Orlean, LA, USA
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] エクソソームを介するEBAG9の伝達は免疫細胞の細胞傷害性を抑制し前立腺がん細胞の免疫系からの回避を引き起こす2018

    • Author(s)
      池田和博、佐藤航、堀江公仁子、井上聡
    • Organizer
      第19回ホルモンと癌研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] エストロゲン応答遺伝子Ebag9欠損マウスにおける骨量減少2018

    • Author(s)
      東浩太郎、柴祥子、池田和博、佐藤航、堀江 公仁子、田中伸哉、井上聡
    • Organizer
      第4回日本骨免疫学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] エストロゲン応答遺伝子Ebag9ノックアウトマウスにおける骨表現型の解析2018

    • Author(s)
      東浩太郎、柴祥子、池田和博、佐藤航、堀江公仁子、田中伸哉、井上聡
    • Organizer
      第18回東京骨関節フォーラム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Proteasome subunit PSMD1 participates in p53 degradation and regulates proliferation of breast cancer cells.2017

    • Author(s)
      Okumura T, Ikeda K, Sato W, Okamoto K, Horie-Inoue K, Takeda S, Inoue S
    • Organizer
      AACR Annual Meeting 2017
    • Place of Presentation
      Washington,D.C. USA
    • Year and Date
      2017-04-01
    • Related Report
      2016 Research-status Report
  • [Presentation] Proteasome subunit PSMD1 participates in p53 degradation and regulates proliferation of breast cancer cells2017

    • Author(s)
      Okumura T, Ikeda K, Sato W, Okamoto K, Horie-Inoue K, Takeda S, Inoue S
    • Organizer
      AACR Annual Meeting 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Identification of hormone-dependent lncRNAs that mediate estrogen signaling pathway in breast cancer2017

    • Author(s)
      Ikeda K, Mitobe Y, Horie K, Inoue S
    • Organizer
      The 43rd Naito Conference, Noncoding RNA : Biology, Chemistry, & Diseases
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] RNAシーケンスによって明らかにされた卵巣がん臨床検体のサブタイプ特異的遺伝子プロファイル2017

    • Author(s)
      長澤さや、池田和博、堀江公仁子、長谷川幸清、竹田省、井上聡
    • Organizer
      第18回ホルモンと癌研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 呼吸鎖超複合体形成はがん増殖能・低酸素抵抗性を促進させる2017

    • Author(s)
      池田和博、堀江公仁子、井上聡
    • Organizer
      第5回がんと代謝研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] Exosome-mediated cancer immune escape exerted by EBAG9 protein エキソソームを介するEBAG9によるがんの免疫逃避2017

    • Author(s)
      Ikeda K, Miyazaki T, Horie-Inoue K, Inoue S
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 乳がんの増殖と生存に関わるエストロゲン応答性長鎖非コードRNAの役割2017

    • Author(s)
      水戸部悠一、堀江公仁子、池田和博、高木清司、鈴木貴、井上聡
    • Organizer
      第25回ステロイドホルモン学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] RNA生理学の学際的アプローチ‐非コードRNAの全貌を明らかにする新たな試み:Long noncoding RNAs that associate with estrogen receptor signaling and contribute to the pathophysiology of endocrine therapy-resistant breast cance(エストロゲン受容体シグナルに関連し治療抵抗性乳がんの病態に関わる長鎖非コードRNA2017

    • Author(s)
      堀江公仁子、水戸部悠一、池田和博、井上聡
    • Organizer
      第40回日本分子生物学会年会conbio2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 技術革新がもたらすがん治療難治性の克服にむけた新しいアプローチ:Regulatory mechanisms of mitochondrial respiratory supercomplex and metabolism in hormone-dependent cancersホルモン依存性がんにおけるミトコンドリア呼吸鎖超複合体と代謝の制御メカニズム2017

    • Author(s)
      池田和博、堀江公仁子、井上聡
    • Organizer
      第40回日本分子生物学会年会conbio2017
    • Related Report
      2017 Research-status Report
  • [Presentation] エクソソームを介してがんの免疫エスケープを引き起こすEBAG9の新しい作用メカニズムと骨における役割2016

    • Author(s)
      井上聡、柴祥子、池田和博、宮崎利明、東浩太郎、田中伸哉、堀江公仁子
    • Organizer
      第2回日本骨免疫学会
    • Place of Presentation
      沖縄県国頭群恩納村
    • Year and Date
      2016-07-06
    • Related Report
      2016 Research-status Report
  • [Presentation] Systemic identification of molecular targets involved in acquired resistance to endocrine therapy for hormone-dependent cancers based on functuional screening and high-throughput sequencing.2016

    • Author(s)
      Ikeda K, Horie K
    • Organizer
      The 41st Naito Conference on "Cancer Heterogeneity and Plasticity: Relevance to Therapeutic Resistance"
    • Place of Presentation
      Sapporo,Japan
    • Year and Date
      2016-07-05
    • Related Report
      2016 Research-status Report
  • [Book] 田村隆明・浦聖恵(編)遺伝子発現制御機構 クロマチン、転写制御、エピジェネティクス2017

    • Author(s)
      池田和博・井上聡
    • Total Pages
      264
    • Publisher
      東京化学同人
    • ISBN
      9784807909179
    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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