Abstract
BackgroundNotch signaling, a critical pathway for tissue development, contributes to tumorigenesis in many tissues; however, the roles of Notch signaling in Intrahepatic Cholangiocarcinoma (ICC) remains unclear. In this study, we evaluated the expression and effects of Notch1 on cell migration in ICC.MethodsMultiple cellular and molecular approaches were performed including gene transfection, siRNA transfection, RT-PCR, Western blotting, Rac activation assays and immunofluorescence.ResultsWe found that Notch1 was up-regulated in ICC tissues and cell lines. The exogenous expression of Notch1 in glioma cells increased their migratory and invasive capacity. Similarly, the suppression of Notch1 expression inactivated Rac1 and inhibited ICC cell migration. Notch1 over expression induced an Epithelial-to-mesenchymal transition (EMT) phenotype that included enhanced expression of α-SMA and Vimentin, loss of E-cadherin expression, morphological changes and cytoskeletal reorganization in ICC cells.ConclusionNotch1 may induce a migratory effect in ICC by causing an epithelial-mesenchymal transition and activating Rac1 and could serve as a novel diagnostic and therapeutic target in patients with ICC.
Highlights
Notch signaling, a critical pathway for tissue development, contributes to tumorigenesis in many tissues; the roles of Notch signaling in Intrahepatic Cholangiocarcinoma (ICC) remains unclear
Notch1 knockdown inactivated Rac1 and inhibited ICC cell migration In reciprocal experiments, we examined whether knocking down endogenous Notch1 would inhibit Rac1 activity and cell migration using Notch1 siRNA
[16] Given that Notch1 expression was associated with ICC metastasis, we further investigated whether a link exists between Notch1 expression and the Epithelial-to-mesenchymal transition (EMT) phenomenon in ICC
Summary
A critical pathway for tissue development, contributes to tumorigenesis in many tissues; the roles of Notch signaling in Intrahepatic Cholangiocarcinoma (ICC) remains unclear. We evaluated the expression and effects of Notch on cell migration in ICC. The pathway is activated through the interaction of a Notch receptor with a Jagged or Delta-like ligand, leading to proteolytic cleavages of the Notch receptor at two distinct sites. This cleavage releases the Notch intracellular domain (ICN), allowing it to enter the nucleus and function as a transcriptional activator. In some tumor types, including skin cancer, human hepatocellular carcinoma and small cell lung cancer, Notch signaling has been shown to play anti-tumor roles rather than oncogenic roles [7]. In the present study, we explored the role of Notch expression, especially in relation to migration, in ICC
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