The EBV-Encoded Oncoprotein, LMP1, Recruits and Transforms Fibroblasts via an ERK-MAPK-Dependent Mechanism

Alexandra M Davis,Mhairi A Morris,Abigail Rapley,Lawrence S Young,Christopher W Dawson

doi:10.3390/pathogens10080982

Alexandra M Davis, Mhairi A Morris + Show 3 more

Open Access

https://doi.org/10.3390/pathogens10080982

Copy DOI

Abstract

Latent membrane protein 1 (LMP1), the major oncoprotein encoded by Epstein–Barr virus (EBV), is expressed at widely variable levels in undifferentiated nasopharyngeal carcinoma (NPC) biopsies, fueling intense debate in the field as to the importance of this oncogenic protein in disease pathogenesis. LMP1-positive NPCs are reportedly more aggressive, and in a similar vein, the presence of cancer-associated fibroblasts (CAFs) surrounding “nests” of tumour cells in NPC serve as indicators of poor prognosis. However, there is currently no evidence linking LMP1 expression and the presence of CAFs in NPC. In this study, we demonstrate the ability of LMP1 to recruit fibroblasts in vitro in an ERK-MAPK-dependent mechanism, along with enhanced viability, invasiveness and transformation to a myofibroblast-like phenotype. Taken together, these findings support a putative role for LMP1 in recruiting CAFs to the tumour microenvironment in NPC, ultimately contributing to metastatic disease.

Highlights

Epstein–Barr virus (EBV) was the first human DNA tumour virus to be identified in the 1960s and is estimated to infect 90–95% of the global population
While little is known about the role of Latent membrane protein 1 (LMP1) in the generation of cancer-associated fibroblasts (CAFs) in nasopharyngeal carcinoma (NPC) [32], in this current study, we demonstrate a role for LMP1 in the recruitment of fibroblasts via an ERK-MAPK-dependent mechanism, with a partial contribution from TGFβ, enhanced fibroblast proliferation, and the subsequent transformation of fibroblasts to a myofibroblast-like phenotype in vitro
Given the numerous synergies between the mechanisms involved in CAF-mediated tumourigenesis and the signalling pathways engaged by LMP1, the idea that LMP1 may be important in driving CAF formation deserves closer inspection [32]

Summary

Introduction

Epstein–Barr virus (EBV) was the first human DNA tumour virus to be identified in the 1960s and is estimated to infect 90–95% of the global population. Infection with EBV in discrete geographical populations carries a higherthan-average risk of developing certain cancers of B cell and epithelial cell origin. Amongst these virus-associated cancers is nasopharyngeal carcinoma (NPC), a type of head and neck cancer that, whilst relatively rare globally (1.2 cases per 100,000 in the global population), exhibits high incidence rates in parts of Southeast Asia, with between 15–50 cases per. LMP1 acts as a constitutively active tumour necrosis factor (TNF) receptor, activating a plethora of mitogenic signalling pathways that are frequently dysregulated in many human cancers, including both the canonical and non-canonical NF-κB pathways, the mitogenic ERK-MAPK and p38-MAPK pathways, the pro-survival PI3K/Akt pathway, the stress-related JNK/SAPK pathway, as well as the Smad-independent activin A/TGFβ signalling cascades, which may contribute to the fibrotic response that drives carcinoma growth and metastases [8,9]

Methods

Results

Discussion

Conclusion