Ikappa B kinase alpha involvement in the development of nasopharyngeal carcinoma through a NF-κB-independent and ERK-dependent pathway.
OBJECTIVE
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.


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.


CONCLUSIONS
Increase in IKKα expression suppresses the progression of NPC through a NF-κB-independent and ERK-dependent pathway.
Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Yuxin
Y
Xie
Yan
Y
Li
Xingchen
X
Peng
Xinchen
X
Peng
Fraser
F
Henderson
Ling
L
Deng
Nianyong
N
Chen
D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma; D045744:Cell Line, Tumor; D019309:Epstein-Barr Virus Nuclear Antigens / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism*; D010766:Phosphorylation
D019309:Epstein-Barr Virus Nuclear Antigens; D016328:NF-kappa B; D051550:I-kappa B Kinase; D020782:Matrix Metalloproteinases
Alternative NF-κB; ERK; Ikappa B kinase alpha; NF-κB; Nasopharyngeal carcinoma; Non-canonical NF-κB; Tumor suppressor