Most of what is known about the biology of Epstein-Barr virus (EBV) relates to its interaction with cells of the B lymphoid lineage. EBV was originally identified on the basis of its association with Burkitt's lymphoma, and the B lymphotropic nature of the virus is confirmed by its ability to readily infect and transform normal resting B cells in vitro (47). The virus, however, can also infect epithelial cells, and this interaction can result in malignant transformation, as exemplified by the consistent association of EBV with nasopharyngeal carcinoma (NPC) and with a proportion of gastric adenocarcinomas (44,47,53). The EBV-induced transformation of B cells in vitro is associated with the expression of two nonpolyadenylated RNAs (EBER1 and EBER2), along with a set of latent viral gene products consisting of six EBV nuclear antigens (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, and EBNA leader protein) and three latent membrane proteins (LMP1, LMP2A, and LMP2B) (67). However, more restricted patterns of latent gene expression are observed in NPC and in EBV-positive gastric adenocarcinomas, where only the EBERs, EBNA1, and LMP2A are consistently expressed and the expression of LMP1 is either variable or absent (44, 67). While the association of EBV with various lymphoid and epithelial malignancies is well documented, the precise contribution of virus infection to the etiology of these tumors remains unknown.LMP1 is the major transforming protein of EBV, being absolutely essential for B-cell transformation (28) and behaving as a classical oncogenic protein in rodent fibroblast transformation assays (61). LMP1 induces the expression of lymphocyte activation antigens (62, 63) and antiapoptotic proteins (Bcl-2, TNFAIP3, and MCL1) (20,32,64) and stimulates the secretion of cytokines such as interleukin-10 (IL-10), among others (58). When expressed in epithelial cells, LMP1 induces the expression of 12). It can transform certain established epithelial cell lines and block the terminal differentiation of the cells (7,8,15,23), and it induces hyperkeratosis when expressed in transgenic mouse epidermis (65). LMP1 also induces the expression of the epidermal growth factor (EGF) receptor (41, 42, 43) and matrix metalloproteinases (35,54,59) and can down-regulate the expression of E-cadherin (16), findings which suggest that LMP1 can modulate signaling pathways that regulate the motile and invasive properties of epithelial cells. This characteristic is of particular relevance given that LMP1-positive NPC tumors are reportedly more aggressive than their LMP1-negative counterparts (24).LMP1 functions as a constitutively activated member of the tumor necrosis factor receptor superfamily, activating a number of signaling pathways in a ligand-independent manner (18, 30). LMP1 activates both the canonical and noncanonical NF-B pathways (37, 49), can induce AP-1 and p38/ATF2 activity (11,12,13,29,50,60), and has been shown previously to activate phosphatidylinositol 3-kinase (PI 3-kinase)/Akt kinase (2, 9, 39).Although the activation of t...

Approximately 20% of global cancer incidence is causally linked to an infectious agent. Epstein-Barr virus (EBV) accounts for around 1% of all virus-associated cancers and is associated with nasopharyngeal carcinoma (NPC). Latent membrane protein 1 (LMP1), the major oncoprotein encoded by EBV, behaves as a constitutively active tumour necrosis factor (TNF) receptor activating a variety of signalling pathways, including the three classic MAPKs (ERK-MAPK, p38 MAPK and JNK/SAPK). The present study identifies novel signalling properties for this integral membrane protein via the induction and secretion of activin A and TGFβ1, which are both required for LMP1’s ability to induce the expression of the extracellular matrix protein, fibronectin. However, it is evident that LMP1 is unable to activate the classic Smad-dependent TGFβ signalling pathway, but rather elicits its effects through the non-Smad arm of TGFβ signalling. In addition, there is a requirement for JNK/SAPK signalling in LMP1-mediated fibronectin induction. LMP1 also induces the expression and activation of the major fibronectin receptor, α5β1 integrin, an effect that is accompanied by increased focal adhesion formation and turnover. Taken together, these findings support the putative role for LMP1 in the pathogenesis of NPC by contributing to the metastatic potential of epithelial cells.

The Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) epithelial cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin–ligand interactions: extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK-MAPK), PI3-Kinase and tyrosine kinases, but not transforming growth factor beta (TGFβ). More detailed analysis implicated the CTAR1-mediated induction of Slug and Twist in LMP1-induced EMT. A key role for β1 integrin signalling in LMP1-mediated ERK-MAPK and focal adhesion kianse (FAK) phosphorylation was observed, and β1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in disease pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype.