Analysis of Annexin A8 in EMT-mediated Oral Cancer Infiltration

• Project/Area Number: 19K19161
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Hiroshima University
• Principal Investigator: Ishida Fumi 広島大学, 医系科学研究科(歯), 専門研究員 (60625979)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: EMT / Partial EMT / Snail / Anexin A / NGS / Annexin / 口腔癌 / 浸潤・転移 / Annexin A8 / AnnexinA8

Outline of Research at the Start

上皮間葉移行（epithelial-to-mesenchymal transition,EMT）を介した癌浸潤・転移のメカニズムを解明してきた。本研究は癌細胞の浸潤開始の動機を増殖のための間質からの栄養確保と想定し、癌細胞と間質との相互作用としての分化の調節（EMT誘導・調節機構）とアンギオジェネシスの媒介が癌浸潤のバリエーションと強度を形成する機構をAnnexinA8を中心に解析する。

Outline of Final Research Achievements

I established an experimental system to reproduce partial EMT (pEMT) and EMT in stages by introducing Snail into an oral squamous cell carcinoma cell-line. The expression of Annexin A8, which was initially the subject of research in this project, could not be detected by the analysis using RNAseq conducted in the final year of this project. However, it was found that Annexin A10 was disappeared by pEMT and was upregulated by EMT, Annexin A6 was gradually upregulated from pEMT to EMT, and Annexin A9 was upregulated by pEMT and EMT.

Academic Significance and Societal Importance of the Research Achievements

口腔扁平上皮癌にSnailを導入し、パーシャルEMT（ｐEMT）とEMTを段階的に再現する実験系を確立し、RNAseqにより全遺伝子の発現をトレース可能となった。膨大な遺伝子発現プロファイルを、公開データベースと統合解析することで単一遺伝子Snailの導入がｐEMTにとどまり、いかにEMTへと移行するのかを突き止める足掛かりとなった。またEMTをpEMTへ逆戻りする実験系を開発できたが、核内受容体の遺伝子発現が要であることが判明し、そのリガンドが癌悪性度を制御できる可能性を発見した。

Research Products

• [Journal Article] Dexamethasone resets stable association of nuclear Snail with LSD1 concomitant with transition from EMT to partial EMT (2022)
  • Author(s): Satoshi Okuda, Nao Yamakado, Koichiro Higashikawa, RyoUetsuki, Fumi Ishida, Andra Rizqiawan, Shigehiro Ono, Kuniko Mizuta, Nobuyuki Kamata, Kei Tobiume
  • Journal Title: Biochemistry and Biophysics Reports Volume: 30 Pages: 101277-101277
  • DOI: 10.1016/j.bbrep.2022.101277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The squamous cell carcinoma cell line OM-1 retains both p75-dependent stratified epithelial progenitor potential and cancer stem cell properties (2021)
  • Author(s): Uetsuki Ryo、Higashikawa Koichiro、Okuda Satoshi、Yamakado Nao、Ishida Fumi、Rizqiawan Andra、Ono Shigehiro、Takechi Masaaki、Mizuta Kuniko、Shigeishi Hideo、Kamata Nobuyuki、Tobiume Kei
  • Journal Title: Biochemistry and Biophysics Reports Volume: 26 Pages: 101003-101003
  • DOI: 10.1016/j.bbrep.2021.101003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] EMT型口腔癌細胞におけるセツキシマブ抵抗性関連遺伝子の網羅的発現解析 (2020)
  • Author(s): 奥田哲史，東川晃一郎，山門奈央，植月亮，石田扶美，小野重弘，奥村俊哉，中原和美，島末洋，武知正晃
  • Organizer: 第65回（公社）日本口腔外科学会総会・学術大会
• [Presentation] EMT型口腔癌細胞における網羅的遺伝子転写産物発現解析 (2020)
  • Author(s): 山門奈央，東川晃一郎，奥田哲史，植月亮，石田扶美，小野重弘，奥村俊哉，中原和美，島末洋，武知正晃
  • Organizer: 第65回（公社）日本口腔外科学会総会・学術大会