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.
Highlights
Cholangiocarcinoma (CC) is a cancer disease which is increasing worldwide [1,2]
To determine activation of Notch signaling in human cholangiocarcinoma cell lines, expression of the Notch downstream target Hes1 was assessed in TFK1, EGI1 and SZ1 by western blotting (Fig. 1A)
The effect of GSI IX on the proliferation of three human cholangiocarcinoma cell lines was determined by MTT assay
Summary
Cholangiocarcinoma (CC) is a cancer disease which is increasing worldwide [1,2]. Representing the second most common primary hepatobiliary cancer shows the need for a better understanding of the tumor development [3]. Most of the CC tumors are adenocarcinomas arising from epithelial cells lining the intra- and extrahepatic biliary tract system [4,5]. Treatment by photodynamic therapy (PDT), systemic chemotherapy and/or radiotherapy are the only options for patients with inoperable disease [9,10,11]. The combination of Gemcitabine and Cisplatin is the standard chemotherapeutic regimen for patients undergoing first line treatment [18,19]. Standard chemotherapies only offer limited benefit and new strategies are still needed to overcome this deadly disease
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