Activation of Notch signaling is required for cholangiocarcinoma progression and is enhanced by inactivation of p53 in vivo

PLoS One. 2013 Oct 30;8(10):e77433. doi: 10.1371/journal.pone.0077433. eCollection 2013.

Abstract

Cholangiocacinoma (CC) is a cancer disease with rising incidence. Notch signaling has been shown to be deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of CC is still not fully explored. In this study, we investigated the effects of Notch inhibition by γ-secretase inhibitor IX (GSI IX) in cultured human CC cell lines and we established a transgenic mouse model with liver specific expression of the intracellular domain of Notch (Notch-ICD) and inactivation of tumor suppressor p53. GSI IX treatment effectively impaired cell proliferation, migration, invasion, epithelial to mesenchymal transition and growth of softagar colonies. In vivo overexpression of Notch-ICD together with an inactivation of p53 significantly increased tumor burden and showed CC characteristics.

Conclusion: Our study highlights the importance of Notch signaling in the tumorigenesis of CC and demonstrates that additional inactivation of p53 in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Bile Duct Neoplasms / drug therapy
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic / drug effects
  • Bile Ducts, Intrahepatic / metabolism
  • Bile Ducts, Intrahepatic / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation / drug effects
  • Cholangiocarcinoma / drug therapy
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology
  • Dipeptides / pharmacology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Infant
  • Male
  • Mice
  • Neoplasm Invasiveness
  • Protein Structure, Tertiary
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Dipeptides
  • Enzyme Inhibitors
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Tumor Suppressor Protein p53
  • Amyloid Precursor Protein Secretases

Grants and funding

Funding was provided by German Research Foundation (PL 468/4-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.