Loss of Notch1 predisposes oro-esophageal epithelium to tumorigenesis

Wanlada Sawangarun, Masita Mandasari, Junko Aida, Kei ichi Morita, Kou Kayamori, Tohru Ikeda, Kei Sakamoto

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Notch signaling functions in diverse developmental and homeostatic processes, including stem cell self-renewal and cell fate determination. Notch1-inactivating mutations are frequently detected in skin and oro-esophageal cancers, suggesting a role for Notch1 as a tumor suppressor. Here, we clarify 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. The epithelium formed normally in N1cKO mice, and although multiple skin tumors were detected at 65 weeks, no tumors developed in the tongue and esophagus. However, 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, indicating the tumor susceptibility of Notch1-deficient epithelium. Notch1 regulates the expression of TERT, and age-related telomere erosion was more rapid in Notch1-deficient basal cells. Our results indicated that although Notch1 deficiency had little effect on squamous epithelium formation, it predisposed the affected epithelium to tumor development, at least in part through accelerated telomere erosion.

Original languageEnglish
Pages (from-to)129-140
Number of pages12
JournalExperimental Cell Research
Volume372
Issue number2
DOIs
Publication statusPublished - 15 Nov 2018

Keywords

  • CRISPR/Cas9
  • Esophageal cancer
  • Head and neck cancer
  • Notch1
  • TERT
  • Telomere

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