Epstein-Barr virus infection and nasopharyngeal carcinoma

Abstract

Epstein-Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways.This article is part of the themed issue 'Human oncogenic viruses'.

Keywords: Epstein–Barr virus; NF-κB activation; latent Epstein–Barr virus genes; nasopharyngeal carcinoma.

Conflict of interest statement

No conflicts of interest are declared.

© 2017 The Author(s).

Figures

Figure 1.

Activation of NF-κB and IL6/STAT3 signalling pathways in NPC cells by multiple EBV-encoded latent gene products. Through binding with TLR3, abundant EBERs could strongly activate both NF-κB and IFN3 signalling pathways. However, the inactivation of TRAF3 by either LMP1 expression or somatic mutation will inhibit IFN3 signalling, thus protecting the cells from the EBER-induced innate immune response. LMP1 also activates the NF-kB signalling pathways through interacting with multiple TRAFs. Distinct NF-κB signals, including p50/p50/BCL3 and p50/RelB, will induce multiple survival genes (A20, survivin) and inflammatory cytokines (IL6). EBNA1 induces the ubiquitous expression of IL6R in NPC cells. The binding of highly expressed IL6 with IL6R results in constitutive activated STAT3 signalling. The activated STAT3 pathway might crosstalk with the altered NF-κB signalling by the upregulation of BCL3 in NPC cells. The common somatic mutations in NPC targeting the NF-κB pathways are also shown.

Figure 2.

Contribution of EBV infection to NPC pathogenesis. EBV infection could drive NPC pathogenesis through multiple pathways. EBV infection promotes a hypermethylation phenotype in the host and induces the inactivation of tumour suppressor genes. EBV-induced hypermethylation may be a host defence response or the direct action of viral genes, such as LMP1, through activation of DNMTs. Both lytic and latent EBV genes may contribute to the development of NPC. The lytic EBV genes may induce genomic instability and stimulate the release of immune-suppressive cytokines for immune evasion of viral infected cells. The expression of latent genes also drives tumorigenesis and the acquisition of stemness in NPC cells. The transformation properties of LMP1 are well documented. Many transformation properties of LMP1 are mediated through NF-κB activation. The important role of BART-miRNAs in NPC pathogenesis, anti-apoptosis and immune evasion is emerging.

Figure 3.

EBV infection and progressive genomic changes drive clonal evolution of nasopharyngeal carcinoma. In NPC, persistent EBV infection in a genetically aberrant epithelial cell and clonal expansion of infected cells are postulated to initiate tumorigenic transformation. Long-term exposure of the nasopharyngeal mucosa to environmental carcinogens (e.g. nitrosamines from salted fish and preserved food) increases DNA damage and induces various somatic genetic alterations in the epithelial cells. Accumulation of driver events including activation of telomerase activity and inactivation of tumour suppressor genes RASSF1A and p16 on chromosomes 3p and 9p facilitate immortalization, genome instability and EBV infection in the histologically normal and/or dysplastic cells. Expression of latency II gene products including EBNA1, LMP1, LMP2A, EBERs and BARTs alters multiple cellular pathways, promotes cell proliferation and modulates the host's microenvironment to drive the clonal expansion of EBV-infected pre-invasive nasopharyngeal epithelial cells. Importantly, EBV facilitates global hypermethylation, which inactivates various cancer-related genes and enhances tumour heterogeneity. During tumour development, the occurrence of acquired mutations in multiple negative regulators in NF-κB signalling alters the activities of various cancer-related genes to enhance tumour heterogeneity. The loss of LMP1 in NPC during progression may be related to acquisition of additional genetic alterations during tumour progression which compensate the functions of LMP1. Further genetic alterations are acquired during tumour progression. In advanced stages, somatic mutations of TP53, RAS and other genes may drive the growth of subclones of NPC cells as local recurrent diseases and distant metastasis after conventional cancer treatment.