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Pathogenesis of oral precancer by NOTCH1

Research Project

Project/Area Number 16K11438
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Morphological basic dentistry
Research InstitutionTokyo Medical and Dental University

Principal Investigator

SAKAMOTO Kei  東京医科歯科大学, 大学院医歯学総合研究科, 講師 (00302886)

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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords口腔癌 / 前癌病変 / 扁平上皮癌 / 癌
Outline of Final Research Achievements

We clarified the contribution of Notch1 deficiency to oro-esophageal tumorigenesis using a physiological experimental model. Tongue and esophageal tumors induced in mice by 4-nitroquinoline-1-oxide (4-NQO) showed pathophysiological similarities to human tumors, including decreased Notch1 expression in the basal cells. We created mutant mice (N1cKO), in which the Notch1 gene was disrupted specifically in the squamous epithelium. Although no tumors developed spontaneously in the tongue and esophagus, 4-NQO-induced tumorigenesis assays revealed that tumor onset occurred earlier in N1cKO mice than in wild-type littermates, and the tumors arose preferentially from the Notch1-negative epithelium. Notch1 regulates the expression of TERT, and age-related telomere erosion was more rapid in Notch1-deficient basal cells. Our results indicated that Notch1 deficiency predisposed the affected epithelium to tumor development, in part through accelerated telomere erosion.

Academic Significance and Societal Importance of the Research Achievements

NOTCH1は扁平上皮の基底細胞に発現し、扁平上皮癌で高頻度で変異が検出される遺伝子だが、その異常が発癌に及ぼす作用は不明な点が多い。本研究から、NOTCH1が扁平上皮の形成に必須ではないものの、テロメアの維持に関連し、NOTCH1の異常が前癌病変および扁平上皮癌の発生を促進する誘因であることを示した。本研究の結果は、正常上皮の腫瘍化リスク、あるいは前癌病変の癌化リスクを評価する指標のひとつとしてNOTCH1の変異の検査が有用であることを示唆する。また癌および前癌病変発生を予防する治療の開発にヒントを与えるものである。

Report

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

    (2 results)

All 2018 2016

All Journal Article (2 results) (of which Peer Reviewed: 1 results,  Acknowledgement Compliant: 1 results)

  • [Journal Article] Loss of Notch1 predisposes oro-esophageal epithelium to tumorigenesis2018

    • Author(s)
      Sawangarun Wanlada、Mandasari Masita、Aida Junko、Morita Kei-ichi、Kayamori Kou、Ikeda Tohru、Sakamoto Kei
    • Journal Title

      Experimental Cell Research

      Volume: 372 Issue: 2 Pages: 129-140

    • DOI

      10.1016/j.yexcr.2018.09.019

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Notch signaling in oral squamous neoplasia.2016

    • Author(s)
      Kei Sakamoto
    • Journal Title

      Pathology International

      Volume: 66(11) Issue: 11 Pages: 609-617

    • DOI

      10.1111/pin.12461

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant

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

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