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Molecular mechanism and impact of loss of primary cilia in PDAC cells

Research Project

Project/Area Number 18K06627
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionNara Institute of Science and Technology

Principal Investigator

Kobayashi Tetsuo  奈良先端科学技術大学院大学, 先端科学技術研究科, 助教 (80433994)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords一次繊毛 / 膵管癌 / 膵管がん
Outline of Final Research Achievements

We established PDAC-originated Panc1 cells devoid of primary cilia by mutating a centriolar protein CEP164. CEP164-mutated cells showed enhanced proliferation in colony formation assay. This was phenocopied by cells treated with Chloral Hydrate which chemically eliminates primary cilia, suggesting that loss of primary cilia promotes PDAC cells proliferation. In addition, CEP164 was co-localized with GLI2 transcription factor of Hedgehog signaling, and required for GLI2 localization at the centriole. CEP164-mutation induced GLI2 activation and in turn, Cyclin D-CDK6 over-expression. Furthermore, it was suggested that CEP164 is involved in K-RAS-signaling-dependent PDAC proliferation.

Academic Significance and Societal Importance of the Research Achievements

膵臓がんの90%以上を占める膵管がんは難治性のがんである。膵管がんでは一次繊毛と呼ばれる細胞小器官が消失している。一次繊毛は多くの細胞増殖シグナルの伝達に介在し、細胞分裂とも関わることから、一次繊毛の消失が膵管がん細胞の増殖に寄与する可能性が考えられる。本研究により、膵管がん細胞における一次繊毛消失が細胞の増殖を亢進させること、さらに中心小体タンパク質CEP164はヘッジホッグシグナルに介在することが見いだされた。ヘッジホッグシグナルは膵管がんの増殖において極めて重要なシグナル経路である。これらの研究成果は、膵管がんの新たな治療法に繋がる可能性がある。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (11 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (2 results) Remarks (1 results)

  • [Int'l Joint Research] Autonomous University of Madrid(スペイン)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] The Ohio State University(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails2021

    • Author(s)
      Barbeito P, Tachibana Y, Martin-Morales R, Moreno P, Mykytyn K, Kobayashi T, Garcia-Gonzalo FR.
    • Journal Title

      Life Science Alliance

      Volume: 4 Issue: 3 Pages: e202000746-e202000746

    • DOI

      10.26508/lsa.202000746

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CEP164 deficiency causes hyperproliferation of pancreatic cancer cells2020

    • Author(s)
      Kobayashi T, Tanaka K, Mashima Y, Shoda A, Tokuda M, Itoh H.
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 8 Pages: 587691-587691

    • DOI

      10.3389/fcell.2020.587691

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 一次繊毛の構築2019

    • Author(s)
      小林 哲夫
    • Journal Title

      腎と透析

      Volume: 87 Pages: 697-700

    • Related Report
      2019 Research-status Report
  • [Journal Article] RABL2 positively controls localization of GPCRs in mammalian primary cilia2019

    • Author(s)
      Dateyama I, Sugihara Y, Chiba S, Ota R, Nakagawa R, Kobayashi T, Itoh H
    • Journal Title

      Journal of Cell Science

      Volume: 132 Issue: 2

    • DOI

      10.1242/jcs.224428

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular mechanism of loss of primary cilia in cancer cells2018

    • Author(s)
      小林 哲夫、伊東 広
    • Journal Title

      生化学

      Volume: 90 Issue: 2 Pages: 169-172

    • DOI

      10.14952/SEIKAGAKU.2018.900169

    • NAID

      40021617407

    • ISSN
      0037-1017
    • Year and Date
      2018-04-25
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] 一次繊毛構築のはじまりの制御機構2018

    • Author(s)
      小林 哲夫
    • Journal Title

      実験医学

      Volume: 36 Pages: 921-925

    • Related Report
      2018 Research-status Report
  • [Presentation] RABファミリー低分子量GTP結合タンパク質群による一次繊毛形成の制御2019

    • Author(s)
      小林 哲夫、 池田 達哉、 伊東 広
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 新規低分子量Gタンパク質Rabl3による一次繊毛形成制御機構の解析2018

    • Author(s)
      池田 達哉、 太田 麗央、 安川 貴文、 小林 哲夫、 伊東 広
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Remarks] 奈良先端科学技術大学院大学先端科学技術研究科バイオサイエンス領域分子情報薬理学ホームページ

    • URL

      http://bsw3.naist.jp/itoh/

    • Related Report
      2020 Annual Research Report 2019 Research-status Report 2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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