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L1CAM-ILK-YAP mechanotransduction drives proliferative activity of epithelial cells in middle ear cholesteatoma.

Research Project

Project/Area Number 16K11186
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Otorhinolaryngology
Research InstitutionJikei University School of Medicine

Principal Investigator

YAMAMOTO-FUKUDA TOMOMI  東京慈恵会医科大学, 医学部, 講師 (40372776)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
KeywordsYAP / ILK / L1CAM / middle ear cholesteatoma / メカノトランクダクション / 中耳真珠腫 / Wnt5a / 耳科学
Outline of Final Research Achievements

Negative pressure in the middle ear is thought to be an important factor related to the etiology of middle ear cholesteatoma.
Integrin-linked kinase (ILK) interacts with extracellular matrix and results in the upregulation of mechanotransduction effector Yes-associated protein (YAP). The L1 cell adhesion molecule (L1CAM) has recently been reported as an activator of the mechanotransduction effectors related to cell proliferation and migration.
We analyzed the expression of ILK, YAP and L1CAM in stretched-middle-ear cultured cells, negative-pressure models and human cholesteatoma tissues. According to the results, the expression of cytoplasmic ILK and nuclear sift of YAP were shown to have increased in the thickened epithelium of the TM under a negative pressure load and the cholesteatoma. As results, we demonstrated the possibility that the stromal L1CAM and epithelial ILK-YAP signaling played an important role in epithelial growth under mechanotransduction in cholesteatoma formation.

Academic Significance and Societal Importance of the Research Achievements

近年,細胞に加わる伸展圧迫などのメカニカルストレスは,胎児発生,加齢/老化,メタボリズム,循環器・運動器維持,腫瘍などで重要なパラメーターであることが明らかにされ,疾患解明の端緒となる新しい知見がもたらされてきている.
本研究は世界で初の中耳真珠腫発症に対するメカニカルストレスの関係を証明することができた。メカニカルストレスにより鼓膜上皮細胞に誘導されたYAP-ILKシグナル発現と上皮下間葉系細胞でのL1CAM発現により鼓膜上皮細胞増殖が活性化されることが証明できた。鼓膜上皮細胞単一異常での発症ではなく間葉系細胞との相互作用にて発症する可能性が示せ、新規保存治療開発関するに新たな知見を示せた。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (16 results)

All 2020 2019 2018 2017

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (11 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Keratinocyte growth factor (KGF) induces stem/progenitor cell growth in middle ear mucosa.2020

    • Author(s)
      Yamamoto-Fukuda T, Akiyama N, Kojima H.
    • Journal Title

      Int J Pediatr Otorhinolaryngol.

      Volume: 128 Pages: 109699-109699

    • DOI

      10.1016/j.ijporl.2019.109699

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of DNA methylation levels in the process of oral mucosal regeneration in a rat oral ulcer model.2020

    • Author(s)
      Akiyama N, Yamamoto-Fukuda T, Yoshikawa M, Kojima H.
    • Journal Title

      Histol Histopathol.

      Volume: 35(3) Pages: 247-256

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Partial Epithelial?Mesenchymal Transition Was Observed Under p63 Expression in Acquired Middle Ear Cholesteatoma and Congenital Cholesteatoma2019

    • Author(s)
      Takahashi Masahiro、Yamamoto-Fukuda Tomomi、Akiyama Naotaro、Motegi Masaomi、Yamamoto Kazuhisa、Tanaka Yasuhiro、Yamamoto Yutaka、Kojima Hiromi
    • Journal Title

      Otology & Neurotology

      Volume: 40 Issue: 8 Pages: e803-e811

    • DOI

      10.1097/mao.0000000000002328

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Keratinocyte Growth Factor (KGF) Modulates Epidermal Progenitor Cell Kinetics through Activation of p63 in Middle Ear Cholesteatoma2018

    • Author(s)
      Yamamoto-Fukuda Tomomi、Akiyama Naotaro、Takahashi Masahiro、Kojima Hiromi
    • Journal Title

      Journal of the Association for Research in Otolaryngology

      Volume: Epub ahead of print Issue: 3 Pages: 1-19

    • DOI

      10.1007/s10162-018-0662-z

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Evaluation of YAP signaling in a rat tympanic membrane under a continuous negative pressure load and in human middle ear cholesteatoma.2017

    • Author(s)
      Akiyama N, Yamamoto-Fukuda T, Yoshikawa M, Kojima H.
    • Journal Title

      Acta Otolaryngol.

      Volume: 137 Issue: 11 Pages: 1158-1165

    • DOI

      10.1080/00016489.2017.1351040

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 中耳真珠腫母膜増殖機構の解析:部分的上皮間葉移行の可能性2019

    • Author(s)
      福田 智美, 穐山 直太郎, 高橋 昌寛, 小島 博己
    • Organizer
      第29回日本耳科学会総会・学術講演会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ラット中耳陰圧モデル鼓膜上皮および中耳真珠腫上皮における ILK-YAP シグナルの解析2019

    • Author(s)
      穐山 直太郎, 福田 智美, 高橋 昌寛, 吉川 衛, 小島 博己
    • Organizer
      第29回日本耳科学会総会・学術講演会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 中耳真珠腫におけるタイトジャンクション関連分子発現の検討2019

    • Author(s)
      高橋 昌寛, 福田 智美, 茂木 雅臣, 穐山 直太郎, 山本 和央, 田中 康広, 山本 裕, 小島 博己
    • Organizer
      第120回 日本耳鼻咽喉科学会総会・学術講演会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Evaluation of YAP signaling in a Rat Tympanic Membrane Under a Continuous Negative Pressure Load and in Human Middle Ear Cholesteatoma2019

    • Author(s)
      Naotaro Akiyama, Tomomi Yamamoto-Fukuda, Masahiro Takahashi, Mamoru Yoshikawa, Hiromi Kojima
    • Organizer
      The Association for Research in Otolaryngology 42th Annual MidWinter Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] KGF過剰発現誘導性中耳真珠腫モデルにおける表皮前駆細胞増殖誘導機構の解析2018

    • Author(s)
      福田 智美, 穐山 直太郎, 高橋 昌寛, 小島 博己
    • Organizer
      第28回日本耳科学会総会・学術講演会
    • Related Report
      2018 Research-status Report
  • [Presentation] 中耳真珠腫間質におけるYAPシグナルの解析2018

    • Author(s)
      穐山 直太郎, 福田 智美, 高橋 昌寛, 吉川 衛, 小島 博己
    • Organizer
      第28回日本耳科学会総会・学術講演会
    • Related Report
      2018 Research-status Report
  • [Presentation] Evaluation of Mechanotransduction in a Rat Tympanic Membrane Under a Continuous Negative Pressure Load and in Human Middle Ear Cholesteatoma.2018

    • Author(s)
      Naotaro Akiyama, Tomomi Yamamoto-Fukuda, Mamoru Yoshikawa, Hiromi Kojima
    • Organizer
      The Association for Research in Otolaryngology 41th Annual MidWinter Meeting
    • Related Report
      2017 Research-status Report
  • [Presentation] Keratinocyte Growth Factor (KGF) Modulates Epidermal Progenitor Cell Kinetics Through activation of p63 in middle ear cholesteatoma.2018

    • Author(s)
      Tomomi Yamamoto-Fukuda, Naotaro Akiyama, Hiromi Kojima
    • Organizer
      The Association for Research in Otolaryngology 41th Annual MidWinter Meeting
    • Related Report
      2017 Research-status Report
  • [Presentation] ラット中耳陰圧モデルおよび弛緩部型真珠腫におけるYAPシグナルの解析2017

    • Author(s)
      穐山 直太郎, 福田 智美, 吉川 衛, 小島 博己
    • Organizer
      第27回日本耳科学会総会・学術講演会
    • Related Report
      2017 Research-status Report
  • [Presentation] 中耳真珠腫発症機序の解明:中耳真珠腫形成における神経堤由来細胞の役割2017

    • Author(s)
      福田智美、穐山直太郎、高橋昌寛、小島博己
    • Organizer
      第27回日本耳科学会総会・学術講演会
    • Related Report
      2017 Research-status Report
  • [Presentation] Novel Experimental model for Negative Pressure in the Middle Ear and Effects of Epithelial-cell Proliferation in the Tympanic Membrane.2017

    • Author(s)
      Naotaro Akiyama, Tomomi Yamamoto-Fukuda, Haruo Takahashi, Hiromi Kojima
    • Organizer
      The Association for Research in Otolaryngology 40th Annual MidWinter Meeting
    • Place of Presentation
      アメリカ、ボルチモア
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2022-12-28  

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