Epstein-Barr Virus Latent Membrane Protein 2A Promotes Invasion of Nasopharyngeal Carcinoma Cells through ERK/Fra-1-Mediated Induction of Matrix Metalloproteinase 9

Abstract

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is highly metastatic, and this malignant feature may be promoted by an EBV oncoprotein, latent membrane protein 2A (LMP2A). Acting as a signal regulator, LMP2A can enhance invasiveness and motility of epithelial cells. Downstream from the LMP2A-triggered signaling events, it is largely unknown what key effector proteins are induced and essentially promote cell invasion. In the present study, we found that in NPC cells, LMP2A upregulated matrix metalloproteinase 9 (MMP9), a metastasis-associated protease. LMP2A increased MMP9 expression at both the mRNA and protein levels. It also activated the MMP9 promoter, in which two AP-1 elements were required for the promoter activation. Among AP-1 transcription factors, Fra-1 was induced by LMP2A and is essential for LMP2A-triggered MMP9 expression. Induction of Fra-1 was dependent on the LMP2A-activated ERK1/2 pathway, and induction of the ERK1/2-Fra-1-MMP9 axis required PY motifs in the amino-terminal domain of LMP2A. Notably, LMP2A-promoted invasion of NPC cells was blocked when MMP9 expression, Fra-1 induction, or ERK1/2 activation was inhibited. In addition, we found an association of LMP2A with MMP9 expression in NPC tumor biopsy specimens, where Fra-1 was a major mediation factor. This study reveals an underlying mechanism of LMP2A-induced cell invasion, from signal transduction to upregulation of a critical protease. Considering that MMP9 can also be upregulated by another EBV oncoprotein, LMP1, this protease may be a pivotal effector at which the EBV-induced, invasion-promoting mechanisms converge, serving as an attractive therapeutic target for NPC treatment.

Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1

“…The LMP2A PY motif mutant constructs were kindly provided by Dr Yao Chang (National Health Research Institutes, Tainan, Taiwan). 27 A series of luciferase reporter plasmids driven by the E47 or PU.1 promoter were constructed in the pCDH-GL3-basic vector. The pcDNA3-E47fD was kindly provided by Dr Rudolf Grosschedl (Max-Planck Institute of Immunobiology, Freiburg, Germany).…”

Epstein–Barr virus latent membrane protein 2A mediated activation of Sonic Hedgehog pathway induces HLA class Ia downregulation in gastric cancer cells

“…Studies of EBV LMP2A till date have implicated this protein in cell migration and invasion (Banerjee et al, 2013;Fotheringham et al, 2012;Lan et al, 2012;Pal et al, 2014) anchorage independent growth (Scholle et al, 1999), Epitheilial Mesenchymal Transition (EMT) (Kong et al, 2010) and also apoptotic resistance (Fukuda and Longnecker, 2004). Our present report highlights the role of LMP2A to induce Sonic Hedgehog pathway dependent HLA Class Ia downregulation in Gastric Cancer cells.…”

Pyruvate dehydrogenase B promoted the growth and migration of the nasopharyngeal carcinoma cells

“…ERK signaling has been reported to be involved in the tumorigenesis of NPC [14,15]. Inhibition of ERK signaling by dasatinib suppressed the invasion of the NPC cells [16].…”