LMP1 antagonizes WNT/β-catenin signalling through inhibition of WTX and promotes nasopharyngeal dysplasia but not tumourigenesis in LMP1B95-8 transgenic mice

Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) can induce cell transformation and tumourigenesis, but the mechanism is not understood. Previous studies have suggested that LMP1 acts through up-regulation of cellular proliferation pathways including the Wnt/beta-catenin pathway, in which beta-catenin is the central effector. Increased levels of beta-catenin coupled with a decrease in E-cadherin lead to reduced cell adhesion. This pathway is antagonized by WTX (Wilms' tumour gene on the X chromosome), which can promote the ubiquitination and degradation of beta-catenin. In the present study, we established L2/LMP1B(95-8)/EGFP transgenic mice to investigate the in vivo role of LMP1. Down-regulation of WTX and E-cadherin was accompanied by increased expression of beta-catenin in these mice. Even though invasive tumours did not develop, dysplasia was seen in the nasopharynx and oropharynx epithelium of these transgenic mice. Analysis of LMP1(+), WTX+, and LMP1 siRNA silenced HNE-1 cell lines demonstrated that WTX could exert a dominant role in LMP1-mediated WNT/beta-catenin pathway regulation. This study indicates that LMP1 antagonizes the WNT/beta-catenin pathway by inhibiting WTX, and this reduction in WTX is associated with epithelial dysplasia via regulation of the WNT/beta-catenin pathway molecules E-cadherin and beta-catenin. Further studies are required for a better understanding of the relationship between LMP1-mediated antagonization of the WNT/beta-catenin pathway and tumourigenesis. Copyright. (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.