Epstein-Barr virus nuclear protein EBNA-3C interacts with the human metastatic suppressor Nm23-H1: A molecular link to cancer metastasis

Abstract

Epstein-Barr virus (EBV) is an oncogenic virus associated with a number of human malignancies including Burkitt lymphoma, nasopharyngeal carcinoma, lymphoproliferative disease and, though still debated, breast carcinoma. A subset of latent EBV antigens is required for mediating immortalization of primary B-lymphocytes. Here we demonstrate that the carboxy-terminal region of the essential latent antigen, EBNA-3C, interacts specifically with the human metastatic suppressor protein Nm23-H1. Moreover, EBNA-3C reverses the ability of Nm23-H1 to suppress the migration of Burkitt lymphoma cells and breast carcinoma cells. We propose that EBNA-3C contributes to EBV-associated human cancers by targeting and altering the role of the metastasis suppressor Nm23-H1.

Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas–a possible mechanism for altering the nm23-H1 activity

“…Recently, Subramanian et al (2001) reported that the Epstein-Barr virus encoded protein EBNA-3C interacts speci®cally with nm23-H1, and that this interaction reversed the ability of nm23-H1 to suppress migration of Burkitts lymphoma and breast carcinoma cells. This is the ®rst evidence that a DNA tumour virus may target a cellular protein associated with metastasis.…”

The suppressor of metastasis Nm23-H1 interacts with the Cdc42 Rho family member and the pleckstrin homology domain of oncoprotein Dbl-1 to suppress cell migration

“…Moreover, We have previously reported at length about an association between Nm23-H1 and the essential Epstein-Barr virus nuclear antigens (EBNA) 1 and 3C. 41,56,57 In those reports, we have shown that Nm23-H1 predominant cytoplasmic localization was dramatically changed to nuclear signals when Nm23-H1 was coexpressed with either EBNA1 or EBNA3C. 41,56 We are currently addressing whether viral proteins such as EBNA1 and EBNA3C, especially EBNA3C shows B cell transformation activity, 1 affect the localization and the function of Nm23-H1, as it relates to signaling through the Rho family GTPase protein complexes.…”

“…The migrated cells were counted at sites in each wells at 40x with an Olympus BX40 light microscope. 56 The data presented at each concentration is the mean of three separate experiments.…”

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“…The current work builds on a voluminous but inconclusive history of potential mechanistic pathways for metastasis suppression by the NME (NM23, nucleoside diphosphate kinase, AWD) family. Considerable evidence indicates that protein:protein interactions with NME modulate components of the metastatic process and in vivo metastasis ( [52][53][54] as examples). The role of NME enzymatic activities has been less certain.…”