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

AbstractLatent 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/β‐catenin pathway, in which β‐catenin is the central effector. Increased levels of β‐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 β‐catenin. In the present study, we established L2/LMP1B95 − 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 β‐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/β‐catenin pathway regulation. This study indicates that LMP1 antagonizes the WNT/β‐catenin pathway by inhibiting WTX, and this reduction in WTX is associated with epithelial dysplasia via regulation of the WNT/β‐catenin pathway molecules E‐cadherin and β‐catenin. Further studies are required for a better understanding of the relationship between LMP1‐mediated antagonization of the WNT/β‐catenin pathway and tumourigenesis. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.