The Epstein-Barr virus encoded LMP1 oncoprotein modulates cell adhesion via regulation of activin A/TGFβ and β1 integrin signalling

Abstract

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.

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

“…67 -increased fibronectin expression and secretion by upregulating the JNK/SAPK pathway. 68 -enhanced TGF-β expression and SMAD2 phosphorylation. 68 EBNA-1 -repression of the tumor suppressor, PTPRK, in Hodgkin lymphoma cells by decreasing SMAD2 levels.…”

“…68 -enhanced TGF-β expression and SMAD2 phosphorylation. 68 EBNA-1 -repression of the tumor suppressor, PTPRK, in Hodgkin lymphoma cells by decreasing SMAD2 levels. 69 -inhibition of the tumor suppressor, βig-h3, and PAI-1 in carcinoma cells via reducing SMAD2 levels.…”

Cancer-Associated Fibroblasts in Undifferentiated Nasopharyngeal Carcinoma: A Putative Role for the EBV-Encoded Oncoprotein, LMP1

“…In addition to the well-known signalling pathways engaged by LMP1 that are classically deregulated in cancer [79], more recent studies have identified novel signalling capabilities for this transforming oncoprotein. LMP1 has previously been shown to modulate the expression and secretion of TGFβ1, as well as enhance the TGFβ-dependent modulation of ERK-MAPK [13,80]. TGFβ is a pleiotropic cytokine that displays context-dependent effects on cell growth, differentiation and maturation, and is an important mediator of CAF-driven tumourigenesis [81].…”

“…These include both the canonical and non-canonical NF-κB pathways [8], the pro-survival PI3K/Akt pathway [9], the stress-related JNK/SAPK pathway [10] and the mitogenic ERK/MAPK [11] and p38-MAPK [12] pathways, which stimulate cell migration and invasion. In addition, LMP1 has been shown to deregulate the pro-fibrotic Smad-independent TGFβ/activin A signalling pathway and overexpress active β1 integrins [13], which may serve to protect epithelial cells from anoikis in order to facilitate metastasis [14].…”

Real-time detection of LMP1/LMP1 interaction in MβCD-induced apoptosis of nasopharyngeal carcinoma cells using FRET method

“…2,3 Because of knockdowning latent membrane protein 1 (LMP1) gene can impair growth and inhibit transformation, 4 LMP1 is considered positively associated with NPC progression. 5 LMP1 plays a variety of roles in NPC progression, such as regulating the releasing of exosomes, 6,7 enhancing expression of matrix metalloproteinases (MMPs), 8 reducing cell-cell adhesion, [9][10][11][12] and inducing abnormal activation of signaling pathways involvement of PI3K, NF-kB, etc. [13][14][15] Previous studies by immuno°uorescence and Immunoblot assays have con¯rmed that LMP1 is an integral membrane protein.…”