Decoy receptor 3, upregulated by Epstein-Barr virus latent membrane protein 1, enhances nasopharyngeal carcinoma cell migration and invasion

Abstract

Decoy receptor 3 (DcR3), a member of tumor necrosis factor receptor superfamily, has been implicated in tumorigenesis through its abilities to modulate immune responses and induce angiogenesis. Epstein-Barr virus (EBV), a ubiquitous gamma-herpesvirus, is associated with malignancies including nasopharyngeal carcinoma (NPC). Previous studies show that DcR3 is overexpressed in EBV-positive lymphomas and Rta, an EBV transcription activator, can upregulate DcR3 in Burkitt lymphoma cell lines. However, DcR3 expression has not been demonstrated in EBV-associated NPC nor have there been any EBV latent genes linked to DcR3 upregulation. Here, we showed DcR3 was overexpressed in NPC. Higher DcR3 expression score and DcR3-positive rate were found in metastatic NPC than in primary NPC tissues, suggesting DcR3 may enhance cell metastatic potential. This hypothesis is supported by our observation that NPC HONE-1 cells overexpressing DcR3 exhibited significant higher migration and invasion abilities in vitro. We found besides Rta, EBV latent membrane protein (LMP) 1 can upregulate DcR3 via nuclear factor-kappaB and phosphatidylinositol 3-kinase-signaling events. Approximate 75% of LMP1-positive NPC tissues overexpressed DcR3, suggesting LMP1 may enhance DcR3 expression in vivo. Data herein suggested that increasing DcR3 expression by LMP1 not only helps EBV-associated cancer cells gain survival advantage by preventing host immune detection but also increases the chance of cancer metastasis by enhancing cell migration and invasion. All these DcR3-mediated events facilitate normal cells to gain cancer hallmarks.

The tumor marker Fascin is induced by the Epstein-Barr virus-encoded oncoprotein LMP1 via NF-κB in lymphocytes and contributes to their invasive migration

“…Both LMP1-mediated transcriptional, posttranscriptional and posttranslational regulation of cellular targets could contribute to the capacity of LMP1 to promote spreading of tumor cells: (1) LMP1 causes loss of junctional plakoglobin in nasopharyngeal carcinoma (NPC) cells and initiates a cadherin switch [[52]]. (2) LMP1 upregulates decoy receptor 3, a member of the TNFR superfamily, which enhances NPC cell migration and invasion [[43]]. (3) LMP1 down-regulates E-cadherin gene expression and induces cell migration activity by using cellular DNA methylation machinery [[45]].…”

LMP1 promotes nasal NK/T-cell lymphoma cell function by eIF4E via NF-κB pathway

“…Studies of LMP1 in nasopharyngeal carcinoma indicated that LMP1 can enhance nasopharyngeal carcinoma cell migration and invasion. Moreover, the human Fab-based immune-conjugate specific for the LMP1 extracellular domain can inhibit nasopharyngeal carcinoma growth both in vitro and in vivo (14,15). These finding suggest that LMP1 may play an important role in the progression of ENKTL.…”

EBV-LMP1-targeted DNAzyme restrains nasopharyngeal carcinoma growth in a mouse C666-1 xenograft model

“…These findings strongly highlight the therapeutic implications of targeting LMP1. LMP1 has been involved in various events of tumor progression, through regulating numerous oncogenic signaling pathways such as nuclear factor-kappaB, phosphatidylinositol 3-kinase, AKT, and mitogen-activated protein kinases [17,25,32,33]. Terrin et al [34] reported that LMP1 simultaneously modulates multiple signal transduction pathways in B cells to transactivate the hTERT promoter and enhance telomerase activity.…”