Objectives: Ikappa B kinase alpha (IKKα) plays an inhibitory role in the development of epithelial-derived tumors. However, its specific function in the development of nasopharyngeal carcinoma (NPC) remains unknown. In this study we identify the role and mechanism of IKKα in IKKα-mediated NPC development.
Material and methods: The effect of IKKα on migration, invasion and tumorigenesis of NPC cell lines was determined using in vitro and in vivo studies. SUNE-1-5-8F cells transfected to overexpress IKKα, SUNE-1-6-10B cells with shRNA-mediated knockdown of IKKα, and three NPC cell lines were studied using Western blotting techniques to compare the major molecules in NF-κB pathways. Additionally, the extracellular signal-regulated kinase (ERK) pathway and matrix metalloproteinases (MMPs) in IKKα-regulated NPC and the effect of Epstein-Barr Nuclear Antigen 1 (EBNA1) on IKKα were examined.
Results: IKKα was underexpressed in highly invasive SUNE-1-5-8F cells compared with non-invasive cells (SUNE-1 and SUNE-6-10B). Overexpression of IKKα in SUNE-1-5-8F cells was achieved through transfection and resulted in inhibited migration and invasion in vitro. Furthermore, IKKα inhibited tumorigenesis in mice inoculated with IKKα-transfected NPC cells in vivo. These processes were independent of the conventional effect of IKKα on Nuclear factor κB (NF-κB) pathways. The ERK pathway was involved in IKKα-related NPC inhibition. Phosphorylation of ERK1/2 and subsequent secretion of MMP-9 were inhibited by the ERK inhibitor U0126 and not regulated by overexpressed IKKα. EBNA1 knockdown using small interfering RNA (siRNA) did not alter the expression of IKKα.
Conclusion: Increase in IKKα expression suppresses the progression of NPC through a NF-κB-independent and ERK-dependent pathway.
Keywords: Alternative NF-κB; ERK; Ikappa B kinase alpha; NF-κB; Nasopharyngeal carcinoma; Non-canonical NF-κB; Tumor suppressor.
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