Pathogenesis of oral precancer by NOTCH1

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K11438
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Morphological basic dentistry
• Research Institution: Tokyo 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
• Keywords: 口腔癌 / 前癌病変

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.

Free Research Field

口腔病理学

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。