The role of NF-[kappa]B activation in immortalization of human nasopharyngeal epithelial cells

Abstract

Undifferentiated nasopharyngeal carcinoma (NPC) is a common cancer among ethnic Cantonese population living in southern China including Hong Kong, but rare in the Western population. NF-κB is a key mediator of inflammatory responses and is frequently activated in human cancers. Activation of NF-κB is common in undifferentiated NPC and may contribute to its pathogenesis. Immortalization is a key hallmark and an early event of cancer cells. The role of NF-κB activation in the immortalization of nasopharyngeal epithelial (NPE) cells is unknown.

Our laboratory has been involved in elucidating molecular events underlying the immortalization of NPE cells. In this study, activation of NF-κB signaling was found to be a common feature in telomerase-immortalized NPE cell lines. NF-κB activation promotes the growth of telomerase-immortalized NPE cells. Suppression of NF-κB activity selectively inhibited the proliferation of immortalized NPE cells but not their parental primary NPE cultures. Furthermore, upregulation of c-Myc and Bmi-1 was also observed in immortalized NPE cells. Inhibition of NF-κB downregulated expression of c-Myc and Bmi-1, suggesting that they are downstream events of NF-κB activation in immortalized NPE cells. The immortalization property of c-Myc and Bmi-1 has been previously reported. In this study, some of pathways upstream of NF-κB have been examined. EGFR and mTORC1 are upstream events of NF-κB activation in immortalized NPE cells. IKKα and IKKβ phosphorylation could activate mTORC1 by phosphorylation of TSC1/2. There may be indirect pathways linking EGFR, mTORC1, and IKK pathways to NF-κB activation. This showed that NF-κB activation is an early event in immortalization of NPE cells and may represent a potential therapeutic target for treatment and prevention of NPC.

Almost 98% of all NPCs are associated with Epstein-Barr virus (EBV) infection. The EBV latent membrane protein 1 (LMP1) is an oncoprotein that is critical for constitutive activation of various signaling pathways, including NF-κB. In this study, a novel nasopharyngeal epithelial cell line, NP44, was immortalized by overexpression of LMP1 protein in combination with telomerase. Activation of EGFR, mTORC1 and NF-κB was observed in LMP1-immortalized NP44 cells. AMPK was also involved in mTORC1 activation in LMP1-immortalized nasopharyngeal epithelial cells.