Oncogenic effects of WNT5A in Epstein-Barr virus-associated nasopharyngeal carcinoma

Abstract

The molecular events that drive the progression of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) are still to be elucidated. Here, we report for the first time the pathogenic significance of an NPC-associated gene, wingless-type MMTV integration site family, member 5A (WNT5A) and the contribution of EBV to its expression. WNT5A is a representative Wnt protein that activates non-canonical Wnt signalling. With regard to its role in carcinogenesis, there is conflicting evidence as to whether WNT5A has a tumour-promoting or tumour-suppressive role. We show that WNT5A is upregulated in primary NPC tissue samples. We also demonstrate that WNT5A expression was dramatically increased in NPC cell lines expressing the EBV-encoded LMP2A gene, suggesting that this EBV-encoded latent gene is responsible for upregulating WNT5A in NPC. In addition, in vitro WNT5A overexpression promotes the proliferation, migration and invasion of NPC cells. Our results not only reveal pro-tumorigenic effects of WNT5A in NPC but also suggest that WNT5A could be an important therapeutic target in patients with EBV-associated disease.

The Wnt pathway: a key network in cell signalling dysregulated by viruses

“…This EBV‐encoded latent gene may also affect β‐catenin independent Wnt signalling. Yap observed LMP2 expression in NPC cells significantly upregulated Wnt5a mRNA levels.…”

Epstein-Barr virus stably confers an invasive phenotype to epithelial cells through reprogramming of the WNT pathway

“…A previous study showed that forced expression of LMP2A dramatically increased WNT5A levels in nasopharyngeal cell lines [ 26 ]. In the NOK cell line, transient or stable transfectants expressing LMP2A failed to increase LEF1 or WNT5A mRNA levels (data not shown).…”

“…EBV infection of epithelial cells also affects the WNT signaling pathway, which is involved in cell differentiation, growth, survival, and movement [ 21 – 23 ]. In NPC, aberrant WNT signaling has been observed that includes increased expression of the WNT ligand, WNT5A, and the frizzled receptor family 7 (FZD7) [ 24 – 26 ]. Furthermore, LMP2A expression in epithelial cells was shown to activate WNT signaling through activation of phosphatidylinositol-3-kinase (PI3K) and the serine/threonine kinase AKT, which inactivates the negative regulator of the WNT signaling pathway, glycogen synthase kinase 3β (GSK3β), resulting in stabilization and nuclear accumulation of β-catenin [ 27 , 28 ].…”

“…Furthermore, LMP2A expression in epithelial cells was shown to activate WNT signaling through activation of phosphatidylinositol-3-kinase (PI3K) and the serine/threonine kinase AKT, which inactivates the negative regulator of the WNT signaling pathway, glycogen synthase kinase 3β (GSK3β), resulting in stabilization and nuclear accumulation of β-catenin [ 27 , 28 ]. In nasopharyngeal cells, LMP2A expression also leads to increased WNT5A, invasion, and proliferation [ 26 ]. Furthermore, the EBV microRNAs, which are highly expressed in NPC can target the WNT signaling pathway [ 29 , 30 ].…”

“…We focused on two members of the WNT signaling pathway, Lymphoid Enhancer Factor 1 (LEF1) and WNT5A, which were substantially increased after EBV infection. Increased expression of LEF1 and WNT5A is observed in NPC [ 26 , 47 ].…”