Abstract
BackgroundClinically, distant metastasis after primary treatment remains a key problem in nasopharyngeal carcinoma (NPC). Thus, identification of the underlying mechanisms and development of novel therapeutic strategies are urgently needed. NOTCH has been shown to function as a tumor promotor that enhances angiogenesis, cancer invasion and metastasis in NPC. However, the precise roles of the four individual NOTCH receptors and their mechanisms of action are unclear.MethodsWe used Western blot analysis, immunofluorescence, immunohistochemical analysis, phalloidin staining, mouse tumor metastatic dissemination models, gene set enrichment analysis, immunoprecipitation assays and a series of functional assays to determine the potential role of NOTCH2 in regulating NPC metastasis.ResultsNOTCH2 expression in the NPC tissues of patients with cervical lymph node metastasis was lower than that of patients without cervical lymph node metastasis. Correspondingly, NOTCH2 expression was low in metastatic and poorly differentiated NPC cells. NOTCH2 expression correlated negatively with survival time in patients with NPC. Suppression of NOTCH2 expression promoted NPC cell metastasis, whereas NOTCH2 overexpression inhibited this process. Furthermore, NOTCH2 attenuated the TRAF6–AKT signaling axis via an interaction between the NOTCH2 intracellular domain (N2ICD) and TRAF6, which inhibited epithelial–mesenchymal transition (EMT) and eventually suppressed NPC metastasis.ConclusionsThese findings reveal that loss of NOTCH2 activates the TRAF6/AKT axis and promotes metastasis in NPC, suggesting that NOTCH2 may represent a therapeutic target for the treatment of NPC.
Highlights
Distant metastasis after primary treatment remains a key problem in nasopharyngeal carcinoma (NPC)
NOTCH2 expression levels are associated with NPC metastasis and patient survival We previously showed that NOTCH signaling accelerated growth, local invasion and metastasis in NPC [15]; we subsequently explored the role of the individual NOTCH receptors in NPC
We evaluated NOTCH2 protein levels using biopsy samples from patients with NPC and a tissue microarray (TMA) containing NPC tissues
Summary
Distant metastasis after primary treatment remains a key problem in nasopharyngeal carcinoma (NPC). NOTCH has been shown to function as a tumor promotor that enhances angiogenesis, cancer invasion and metastasis in NPC. Nasopharyngeal carcinoma (NPC) is a poorly understood epithelial malignancy that is relatively common in certain regions of South China, Southeast Asia and North Africa [1,2,3]. 30 to 40% of patients suffer distant metastases within 4 years [7, 8], which are associated with a very poor prognosis, mainly because the tumor cells develop chemo- and radioresistance [9]. A comprehensive understanding of the molecular mechanisms that promote progression and metastasis in NPC may help to design more effective, targeted treatment strategies
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