Significance of NF-kB activation in immortalization of nasopharyngeal epithelial cells

Abstract

NF-κB is a key regulator of inflammatory response and is frequently activated in human cancer including the undifferentiated nasopharyngeal carcinoma (NPC), which is common in Southern China including Hong Kong. Activation of NF-κB is common in NPC and may contribute to NPC development. The role of NF-κB activation in immortalization of nasopharyngeal epithelial (NPE) cells, which may represent an early event in NPC pathogenesis, is unknown. Examination of NF-κB activation in immortalization of NPE cells is of particular interest as the site of NPC is often heavily infiltrated with inflammatory cellular components. We found that constitutive activation of NF-κB signaling is a common phenotype in telomerase-immortalized NPE cell lines. Our results suggest that NF-κB activation promotes the growth of telomerase-immortalized NPE cells, and suppression of NF-κB activity inhibits their proliferation. Furthermore, we observed upregulation of c-Myc, IL-6 and Bmi-1 in our immortalized NPE cells. Inhibition of NF-κB downregulated expression of c-Myc, IL-6 and Bmi-1, suggesting that they are downstream events of NF-κB activation in immortalized NPE cells. We further delineated that EGFR/MEK/ERK/IKK/mTORC1 is the key upstream pathway of NF-κB activation in immortalized NPE cells. Elucidation of events underlying immortalization of NPE cells may provide insights into early events in pathogenesis of NPC. The identification of NF-κB activation and elucidation of its activation mechanism in immortalized NPE cells may reveal novel therapeutic targets for treatment and prevention of NPC. What's new? Activation of NF-κB is a common molecular feature in nasopharyngeal cancer (NPC). Yet, it remains unclear whether nuclear factor signaling, through its anti-apoptotic and pro-survival activities, influences the immortalization of nasopharyngeal epithelial (NPE) cells, an essential event in NPC development. In this study, the canonical NF-κB pathway was observed as being constitutively activated in NPE cells immortalized via ectopic telomerase expression. Activation of EGFR was identified as a key upstream event leading to MEK/ERK/IKK/mTOR/NF-κB signaling. Knowledge of this pathway and its role in facilitating NPE cell proliferation could help shed light on early events in NPC. © 2015 UICC.