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

Introduction: Cholangiocarcinoma (CC) is a cancer disease which is increasing worldwide. The Notch signalling pathway is involved in the development and progression of several malignancies. However, the role of this Notch signaling in the carcinogenesis of CC is still not fully explored. In our study, we investigated the effects of Notch inhibition by gamma -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.

Methods: We analyzed the effect of GSI IX by testing different dosages on CC's growth and epithelial plasticity by using WST-1 assay, wound healing assay, invasion assay, colony formation assay and apoptosis assay respectively. In addition, we generated mice with a liver specific over expression of the activated form of the Notch1 receptor and inactivation of the tumor suppressor gene p53 (AlbCre Rosa26Notch1IC).

Results: Our work reveals that GSI IX can impair cell proliferation, EMT, migration and invasion in human CC cell lines. Notch activation and loss of p53 together is showing an enhanced tumor development in vivo.

Conclusion: Our study highlights the importance of Notch signaling in the carcinogenesis of CC and demonstrates that additional inactivation of p53 in vivo influences the development of an aggressive tumor progression.