Recent advances in nasopharyngeal carcinoma (NPC) and EBV infection

Abstract

Undifferentiated nasopharyngeal carcinoma (NPC) is endemic among southern Chinese and is closely associated with Epstein-Barr virus (EBV) infection. The role of EBV in the pathogenesis of NPC remains enigmatic after long years of research. Most intriguingly, EBV episomes are readily lost in NPC cell lines propagated in culture strongly suggesting that EBV infection per se does not confer proliferation advantage to infected NPC cells. Rapid advances have been made in recent years provided new insights to the pathological role of EBV in NPC. EBV infection of normal pharyngeal epithelial cells is predominantly lytic in nature. Interestingly, EBV infection in NPC is predominantly latent. The conversion of lytic infection of EBV to latent infection may represent a crucial process in transformation of premalignant nasopharyngeal epithelial cells into cancer cells. Latent EBV infection and high expression of EBV-encoded BART transcripts and its encoded BARTmicroRNAs are postulated to contribute to the tumorigenic properties of EBV in infected NPC cells. While the genetic alterations and key signaling pathways in NPC supporting latent EBV infection remains to be identified. Recent advances in genomic profiling studies have identified specific genomic landscapes of NPC providing important insights to the role of EBV infection in NPC. Strikingly, atypical activation of NFkB signaling involving inactivation of its upstream negative regulator including CYLD, TRAF3 and NFKB1A. Interestingly, mutations of these negative regulators of NF-κB signaling are mutually exclusive with the expression of the EBV-encoded LMP1 in NPC. The oncogenic properties LMP1 have been wellestablished. LMP1 is known to be a potent activator of NF-κB signaling mediating many downstream transformation properties of LMP1. The mutually exclusive relation of mutation of negative regulators of NF-κB signaling with LMP1 expression in NPC strongly suggests the importance of NF-κB activation in NPC pathogenesis. Recently, EBV from NPC origin was successfully isolated and become available for infection study. The NPC-derived EBV (named as M81) has unique infection properties including spontaneously lytic reactivation in infected B cells and high infection efficiency in epithelial cells. This finding has stimulated interests to examine the long-postulated but poorly defined hypothesis that specific type of EBV may be involved with NPC development in endemic area. Furthermore, recent profiling of EBV sequences indicated that EBV in NPC cluster together and are distinct from EBV isolated from lymphoma of B cell origin. Another advance is the establishment of premalignant nasopharyngeal epithelial cells and new EBV+ve NPC xenografts and cell lines for investigations. The lack of representative NPC cell line harboring EBV has been hampering research to elucidate the pathogenic role of EBV infection in NPC. The establishment of new EBV+ve NPC cell lines also enable cloning of more NPC-derived EBV for investigation. In this presentation, I will review these new advances and their impacts on the NPC and EBV infection.