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Notch1-Hes1 signalling axis in the tumourigenesis of biliary neuroendocrine tumours
  1. Kenichi Harada1,
  2. Yasunori Sato1,
  3. Hiroko Ikeda2,
  4. Maylee Hsu1,
  5. Saya Igarashi1,
  6. Yasuni Nakanuma1
  1. 1Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan
  2. 2Division of Pathology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
  1. Correspondence to Dr Kenichi Harada, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan; kenichih{at}


Aims Biliary neuroendocrine tumours (NETs) are rare and mostly exist as a component of mixed adenoneuroendocrine carcinomas (MANECs). Although the NET component in biliary MANECs is generally more malignant and clinically more important to the prognosis than the ordinary adenocarcinomatous component, the histogenesis of biliary NET has not been clarified. In this study, the role of the Notch1-Hes1 signalling axis in the histogenesis of biliary NETs was examined.

Methods Immunohistochemistry for Notch1, its ligand Jagged1 and Hes1 was performed using surgical specimens from 11 patients with biliary MANEC. Moreover, after the knock-down of Notch1 mRNA expression in a cholangiocarcinoma cell line, the expression of chromogranin A (a neuroendocrine marker) and Ascl1 (a neuroendocrine-inducing molecule inhibited by activated Hes1) was examined by quantitative PCR.

Results Histological examination revealed that the adenocarcinomatous components were predominately located at the luminal surface of the MANEC and the majority of stromal invasion involved NET components. Ordinary adenocarcinomas and non-neoplastic biliary epithelium constantly expressed Notch1, Jagged1 and Hes1, but the expression of Notch1 and Hes1 was decreased or absent in NET components, suggesting interference with the Notch1-Hes1 signalling axis in biliary NET. Moreover, in the cholangiocarcinoma cell line in which the expression of Notch1 mRNA was knocked down, the mRNA expression of Ascl1 and chromogranin A was increased.

Conclusions The Notch1-Hes1 signalling axis suppresses neuroendocrine differentiation and maintains tubular/acinar features in adenocarcinoma and non-neoplastic epithelium in the biliary tree. Moreover, a disruption of this signalling axis may be associated with the tumourigenesis of NETs in biliary MANEC.

  • Carcinoma
  • Cholangiocarcinoma
  • Liver Cancer
  • Neuroendocrine Tumours

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