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

• Project/Area Number: 18K06627
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Nara 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: ¥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。

Research Products

• [Int'l Joint Research] Autonomous University of Madrid(スペイン)
• [Int'l Joint Research] The Ohio State University(米国)
• [Journal Article] HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CEP164 deficiency causes hyperproliferation of pancreatic cancer cells (2020)
  • 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
  • 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
• [Journal Article] RABL2 positively controls localization of GPCRs in mammalian primary cilia (2019)
  • 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
  • Peer Reviewed
• [Journal Article] Molecular mechanism of loss of primary cilia in cancer cells (2018)
  • 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
  • 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
• [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
• [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
• [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/