ReviewThe role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (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.
References (159)
Epstein-Barr virus in the pathogenesis of NPC
Semin Cancer Biol
(2002)- et al.
The significance of LMP1 expression in nasopharyngeal carcinoma
Semin Cancer Biol
(2002) - et al.
Expression of the BNLF-1 oncogene of Epstein-Barr virus in the skin of transgenic mice induces hyperplasia and aberrant expression of keratin 6
Cell
(1990) - et al.
DNA tumour viruses promote tumour cell invasion and metastasis by deregulating the normal processes of cell adhesion and motility
Eur J Cell Biol
(2008) - et al.
Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr virus-encoded latent membrane protein1 coregulates interleukin-6 and interleukin-8 production
J Biol Chem
(1999) - et al.
Epstein-Barr virus: LMP1 masquerades as an active receptor
Curr Biol
(1998) - et al.
Epstein-Barr virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodelling
J Biol Chem
(2003) - et al.
Epstein-Barr virus latent membrane protein 1 mediates phosphorylation and nuclear translocation of annexin A2 by activating PKC pathway
Cell Signal
(2007) - et al.
BS69 negatively regulates the canonical NF-kappaB activation induced by Epstein-Barr virus-derived LMP1
FEBS Lett
(2009) - et al.
BS69 cooperates with TRAF3 in the regulation of Epstein-Barr virus-derived LMP1/CTAR1-induced NF-κB activation
FEBS Lett
(2010)
Genetic and epigenetic changes in nasopharyngeal carcinoma
Sem Cancer Biol
Latent membrane protein 1 of Epstein-Barr virus regulates p53 phosphorylation through MAP kinases
Cancer Lett
MDM2 expression in EBV-infected nasopharyngeal carcinoma cells
Lab Invest
The Id proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation
Virology
The psoriatic transcriptome closely resembles that induced by interleukin-1 in cultured keratinocytes: dominance of innate immune responses in psoriasis
Am J Pathol
Downregulation and abnormal expression of E-cadherin and beta-catenin in nasopharyngeal carcinoma: close association with advanced disease stage and lymph node metastasis
Hum Pathol
Induction of matrix metalloproteinases by Epstein-Barr virus latent membrane protein 1 isolated from nasopharyngeal carcinoma
Biomed Pharmacother
Transcriptional repression of tissue inhibitor of metalloproteinase-3 by Epstein-Barr virus latent membrane protein 1 enhances invasiveness of nasopharyngeal carcinoma cells
Oral Oncol
Induction of c-Met proto-oncogene by Epstein-Barr virus latent membrane protein-1 and the correlation with cervical lymph node metastasis of nasopharyngeal carcinoma
Am J Pathol
Expression and clinical significance of latent membrane protein-1, matrix metalloproteinase-1 and Ets-1 transcription factor in tunisian nasopharyngeal carcinoma patients
Arch Med Res
Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production
J Biol Chem
Epstein-Barr virus: 40 years
Nat Rev Cancer
Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma
N Engl J Med
Epstein-Barr virus-encoded LMP1 induces a hyperproliferative and inflammatory gene expression programme in cultured keratinocytes
J Gen Virol
Epstein-Barr virus latent membrane protein 1: structure and functions
J Biomed Sci
Role of Epstein-Barr virus encoded latent membrane protein 1 in the carcinogenesis of nasopharyngeal carcinoma
Cell Mol Immunol
Role of the Epstein-Barr virus-encoded latent membrane protein 1, LMP1, in the pathogenesis of nasopharyngeal carcinoma
Future Oncol
The latent membrane protein 1 oncogene modifies B-cell physiology by regulating autophagy
Oncogene
Transformation of Madin–Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth
Oncogene
Epstein-Barr virus latent membrane protein 1 CTAR1 mediates rodent and human fibroblast transformation through activation of PI3K
Oncogene
Epstein-Barr virus-encoded LMP1 regulates epithelial cell motility and invasion via the ERK-MAPK pathway
J Virol
Intracellular signaling molecules activated by Epstein-Barr virus for induction of interferon regulatory factor 7
J Virol
Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway
Oncogene
Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKKα-dependent non-canonical NF-κB activation
Proc Natl Acad Sci U S A
Induction of epidermal growth factor receptor expression by Epstein-Barr virus latent membrane protein 1 C-terminal-activating region 1 is mediated by NF-kB p50 homodimer/Bcl-3 complexes
J Virol
Epstein-Barr virus latent membrane protein 1 modulates distinctive NF-kB pathways through C-terminus-activating region 1 to regulate epidermal growth factor receptor expression
J Virol
The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-κB
Proc Natl Acad Sci USA
Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1)
Oncogene
Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade
EMBO J
Epstein-Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2
J Virol
LMP1 signal transduction differs substantially from TNF receptor 1 signaling in the molecular functions of TRADD and TRAF2
EMBO J
BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway
Mol Cell Biol
Unique signaling properties of CTAR1 in LMP1-mediated transformation
J Virol
Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor through effects on Bcl-3 and STAT3
J Virol
Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCδ
J Virol
IRF7: activation, regulation, modification and function
Genes Immun
Interferon regulatory factor 7 is activated by a viral oncoprotein through RIP-dependent ubiquitination
Mol Cell Biol
Interferon regulatory factor 7 regulates expression of Epstein-Barr virus latent membrane protein 1: a regulatory circuit
J Virol
The A20 deubiquitinase activity negatively regulates LMP1 activation of IRF7
J Virol
Negative regulation of Epstein-Barr virus latent membrane protein 1-mediated functions by the bone morphogenetic protein receptor IA-binding protein
BRAM1 J Biol Chem
Cited by (267)
Oncoviruses: How do they hijack their host and current treatment regimes
2023, Biochimica et Biophysica Acta - Reviews on Cancer