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

Dan Dan Zhu, Jun Zhang, Wen Deng, Yim Ling Yip, Hong Lok LUNG, Chi Man Tsang, Wai Tak Law, Jie Yang, Victoria Ming Yi Lau, Wai Ho Shuen, Maria Li Lung, Annie Lai Man Cheung, Sai Wah Tsao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1175-1185
Number of pages11
JournalInternational Journal of Cancer
Volume138
Issue number5
DOIs
Publication statusPublished - 1 Mar 2016

Scopus Subject Areas

  • Oncology
  • Cancer Research

User-Defined Keywords

  • ERK1/2
  • immortalization
  • mTOR
  • nasopharyngeal carcinoma
  • NF-κB

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