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Abstract
The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) protein is expressed in all virus-associated malignancies, where it performs an essential role in the maintenance, replication and transcription of the EBV genome. In recent years, it has become apparent that EBNA1 can also influence cellular gene transcription. Here, we demonstrate that EBNA1 is able to stimulate the expression of the Transforming growth factor-beta (TGFβ) superfamily member, bone morphogenic protein 2 (BMP2), with consequential activation of the BMP signalling pathway in carcinoma cell lines. We show that BMP pathway activation is associated with an increase in the migratory capacity of carcinoma cells, an effect that can be ablated by the BMP antagonist, Noggin. Gene expression profiling of authentic EBV-positive nasopharyngeal carcinoma (NPC) tumours revealed the consistent presence of BMP ligands, established BMP pathway effectors and putative target genes, constituting a prominent BMP “signature” in this virus-associated cancer. Our findings show that EBNA1 is the major viral-encoded protein responsible for activating the BMP signalling pathway in carcinoma cells and supports a role for this pathway in promoting cell migration and possibly, metastatic spread.
Highlights
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is aetiologically linked to malignancies of both lymphoid and epithelial origin, reflecting the natural tropism of the virus in vivo [1,2]
To gain an overall impression of bone morphogenic protein (BMP) pathway activity in nasopharyngeal carcinoma (NPC), normalised array intensities were subjected to dChip software analysis and R Studio was used to generate a heatmap displaying differentially regulated genes associated with the BMP pathway
It is feasible that the enhanced BMP signalling activity we have found in NPC may contribute to bone metastasis, which is associated with more advanced cases and with poor prognosis in this tumour [70]
Summary
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is aetiologically linked to malignancies of both lymphoid and epithelial origin, reflecting the natural tropism of the virus in vivo [1,2]. The virus exploits the B-cell differentiation programme to persist within the resting memory. B-cell compartment of the immunocompetent host as a lifelong asymptomatic infection [3,4]. EBV establishes long-term latency in the B-lymphocyte compartment, while it is capable of replicating in both B-lymphocytes and epithelial cells [1]. It possesses the unique ability to transform resting B-lymphocytes in vitro into continuously proliferating lymphoblastoid cell lines (LCLs) [5], indicative of its oncogenic potential. In the context of immunosuppression or other cofactors such as malaria, EBV is associated with the development of lymphomas predominantly of Pathogens 2020, 9, 594; doi:10.3390/pathogens9070594 www.mdpi.com/journal/pathogens. The aberrant establishment of latent non-replicative EBV infection in epithelial cells contributes to the development of nasopharyngeal carcinoma (NPC) and a subset of gastric carcinomas
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