ABSTRACT
Notch pathway is a highly conserved cell signaling system that plays very important roles in controlling multiple cell differentiation processes during embryonic and adult life. Multiple lines of evidence support the oncogenic role of Notch signaling in several human solid cancers; however, the pleiotropic effects and molecular mechanisms of Notch signaling inhibition on nasopharyngeal carcinoma (NPC) remain unclear. In this study, we evaluated Notch1 expression in NPC cell lines (CNE1, CNE2, SUNE1, HONE1, and HK1) by real-time quantitative PCR and Western blot analysis, and we found that CNE1 and CNE2 cells expressed a higher level of Notch1 compared with HONE1, SUNE1, and HK1 cells. Then Notch1 expression was specifically knocked down in CNE1 and CNE2 cells by Notch1 short hairpin RNA (shRNA). In Notch1 knockdown cells, cell proliferation, migration, and invasion were significantly inhibited. The epithelial-mesenchymal transition of tumor cells was reversed in Notch1-shRNA-transfected cells, accompanied by epithelioid-like morphology changes, increased protein levels of E-cadherin, and decreased expression of vimentin. In addition, knockdown of Notch1 markedly inhibited the expression of urokinase plasminogen activator (uPA) and its receptor uPAR, and chemokines C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 16, indicating that these factors are downstream targets of Notch1. Furthermore, deleting uPA expression had similar effects as Notch1. Finally, knockdown of Notch1 significantly diminished CNE1 cell growth in a murine model concomitant with inhibition of cell proliferation and induction of apoptosis. These results suggest that Notch1 may become a novel therapeutic target for the clinical treatment of NPC.
Subject(s)
Chemokine CCL2/genetics , Chemokine CXCL16/genetics , Nasopharyngeal Carcinoma/genetics , Receptor, Notch1/genetics , Urokinase-Type Plasminogen Activator/genetics , Animals , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , Gene Knockdown Techniques , Heterografts , Humans , Mice , Nasopharyngeal Carcinoma/pathology , Neoplasm Metastasis , Neoplasm Proteins/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology , Receptor, Notch1/antagonists & inhibitors , Signal TransductionABSTRACT
Despite advances in surgery, imaging, chemotherapy, and radiotherapy, the poor overall cancer-related death rate remains unacceptable. Novel therapeutic strategies are desperately needed. Nowadays, targeted therapy has become the most promising therapy and a welcome asset to the cancer therapeutic arena. There is a large body of evidence demonstrating that the Notch signaling pathway is critically involved in the pathobiology of a variety of malignancies. In this review, we provide an overview of emerging data, highlight the mechanism of the Notch signaling pathway in the development of a wide range of cancers, and summarize recent progress in therapeutic targeting of the Notch signaling pathway.
