Review
The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC)

https://doi.org/10.1016/j.semcancer.2012.01.004Get rights and content

Abstract

Although frequently expressed in EBV-positive malignancies, the contribution of the oncogenic latent membrane proteins, LMP1 and LMP2, to the pathogenesis of nasopharyngeal carcinoma (NPC) is not fully defined. As a key effector in EBV-driven B cell transformation and an established “transforming” gene, LMP1 displays oncogenic properties in rodent fibroblasts and induces profound morphological and phenotypic effects in epithelial cells. LMP1 functions as a viral mimic of the TNFR family member, CD40, engaging a number of signalling pathways that induce morphological and phenotypic alterations in epithelial cells. Although LMP2A plays an essential role in maintaining viral latency in EBV infected B cells, its role in epithelial cells is less clear. Unlike LMP1, LMP2A does not display “classical” transforming functions in rodent fibroblasts but its ability to engage a number of potentially oncogenic cell signalling pathways suggests that LMP2A can also participate in EBV-induced epithelial cell growth transformation. Here we review the effects of LMP1 and LMP2 on various aspects of epithelial cell behaviour highlighting key aspects that may contribute to the pathogenesis of NPC.

Introduction

Epstein-Barr virus (EBV) is a human gammaherpesvirus found as a widespread and largely asymptomatic infection throughout the world. The virus exploits the physiology of normal B cell differentiation to persist within the memory B cell pool of the immunocompetent host as a life-long latent infection. EBV replication occurs in both B cells and in mucosal epithelium lining the nasopharynx. It is the aberrant establishment of latent EBV infection at these sites that results in the development of both lymphoid and epithelial tumours [1]. The oncogenic potential of EBV was demonstrated through its association with multiple human malignancies including Burkitt's lymphoma (BL), NPC, Hodgkin's lymphoma (HL), post-transplant lymphoproliferative disease (PTLD), some NK/T-cell lymphomas, and a proportion of gastric carcinomas [1]. Different forms of EBV latent gene expression are observed in these tumours. In NPC EBV latent gene expression is restricted to EBNA1, the LMP2A/B proteins, the EBER and BamHIA transcripts with variable expression of the LMP1 protein [2]. The presence of monoclonal EBV episomes in NPC indicates that virus infection preceded the clonal expansion of the malignant cell population [2]. Limited analysis of premalignant lesions in the nasopharynx also found monoclonal EBV episomes along with LMP1 expression suggesting a role for this viral oncogene in the early stages of NPC pathogenesis [3].

Section snippets

Latent membrane protein 1 (LMP1)

LMP1 is one of five key EBV-encoded viral proteins required for B cell immortalisation [1]. While early experiments performed in rodent fibroblasts identified LMP1 as a viral “transforming” gene, the advent of recombinant EBV technology established the requirement for LMP1 in EBV-mediated B cell immortalisation [1]. While expression of LMP1 in human epithelial cells is not normally associated with growth transformation, LMP1 does exert a variety of growth-promoting effects in this cell type [4]

Expression of LMP2 in NPC

Unlike LMP1, expression of LMP2A appears to be more consistent in NPC. Early studies confirmed expression of LMP2A mRNA in greater than 98% of NPC cases by RT-PCR, while expression of LMP2B appeared lower, and mirrored that of LMP1 [118], [119]. Immunohistochemical staining has confirmed expression of LMP2A protein in greater than 50% of NPC cases [120], [121], values which are probably an under-estimate due to the low levels of LMP2A expression in NPC.

LMP2 structure and localisation

The EBV-encoded LMP2 gene encodes two

Conclusions

There is now strong evidence supporting a role for EBV in the pathogenesis of NPC. Although early studies on LMP1 and LMP2 function were performed in B cells and rodent fibroblast systems, it is now clear that both LMP1 and LMP2 exert profound effects on the behaviour of epithelial cells, impacting on a variety of cellular processes such as proliferation, survival, motility and invasion. The limited availability of appropriate epithelial cell lines and in vivo model systems has hampered

Conflict of interest

The authors declare that there are no conflicts of interest.

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