Please cite this article in press as: Dawson CW, et al. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol (2012), doi:10.1016/j.semcancer.2012.01.004 ARTICLE IN PRESS G Model YSCBI-971; No. of Pages 10 Seminars in Cancer Biology xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Seminars in Cancer Biology jou rn al h om epa g e: www.elsevier.com/locate/semcancer Review The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC) Christopher W. Dawson ∗ , Rebecca J. Port, Lawrence S. Young Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom a r t i c l e i n f o Keywords: EBV LMP1 LMP2 NPC a b s t r a c t 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. © 2012 Elsevier Ltd. All rights reserved. 1. 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 repli- cation 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 multi- ple 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 expres- sion 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 pro- tein [2]. The presence of monoclonal EBV episomes in NPC indicates that virus infection preceded the clonal expansion of the malig- nant cell population [2]. Limited analysis of premalignant lesions in the nasopharynx also found monoclonal EBV episomes along with ∗ Corresponding author. Tel.: +44 121 414 4484; fax: +44 121 414 4486. E-mail address: c.w.dawson@bham.ac.uk (C.W. Dawson). LMP1 expression suggesting a role for this viral oncogene in the early stages of NPC pathogenesis [3]. 2. 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 require- ment for LMP1 in EBV-mediated B cell immortalisation [1]. While expression of LMP1 in human epithelial cells is not normally asso- ciated with growth transformation, LMP1 does exert a variety of growth-promoting effects in this cell type [4]. Whereas targeted expression to the epidermis of transgenic mice is associated with epidermal hyperplasia [5], expression in non-transformed epithe- lial cell lines induces a cellular phenotype similar to “wounded” or psoriatic keratinocytes [6]. When expressed in tumourigenic epithelial cells, LMP1 potentiates anchorage-independent growth and greatly enhances cell motility and invasion [4,7–9]. Taken as a whole, these findings demonstrate that LMP1 can induce pro- found effects in epithelial cells, many of which may account for its oncogenic properties. 2.1. LMP1 structure and function Recent reviews have described in detail the structural and functional aspects of LMP1 signalling in epithelial cells [4,7–9]. 1044-579X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2012.01.004