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Twist and Epithelial-Mesenchymal Transition Are Induced by the EBV Oncoprotein Latent Membrane Protein 1 and Are Associated with Metastatic Nasopharyngeal Carcinoma

¹ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; ² Department of Otolaryngology, School of Medicine, Kanazawa University, Kanazawa, Japan; ³ Whitehead Institute for Biomedical Research, Cambridge, Massachusetts; and ⁴ Pharmacologie Experimentale et Clinique, Institut Federatif de Recherche Saint Louis, Institut de Gënëtique Moleculaire, Paris, France

Requests for reprints: Joseph S. Pagano, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Room 32-020, CB 7295, Chapel Hill, NC 27599-7295. Phone: 919-966-8644; Fax: 919-966-9673; E-mail: joseph_pagano{at}med.unc.edu.

Nasopharyngeal carcinoma (NPC), an EBV-associated malignancy, is highly metastatic compared with other head and neck tumors, perhaps because of its viral link. Here, we show that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), induces epithelial-mesenchymal transition (EMT) via Twist, a master transcriptional regulator in embryogenesis and newly implicated in metastasis, which, in turn, are likely to contribute to the highly metastatic character of NPC. LMP1 could induce EMT and its associated cell motility and invasiveness in a cell culture model, whereas expression of Twist small interfering RNA reversed LMP1-induced EMT. In diverse EBV-infected cell lines, expression of Twist correlates with expression of LMP1. Dominant-negative LMP1 could suppress Twist expression in EBV-positive cells, whereas LMP1 could induce Twist in EBV-negative nasopharyngeal cells. LMP1 signals through the nuclear factor-B pathway, and an IB superrepressor inhibited induction of Twist by LMP1. Finally, in human NPC tissues, expression of Twist and LMP1 is directly correlated and expression of Twist is associated with metastasis clinically. These results suggest that induction of Twist by a human viral oncoprotein LMP1 directly contributes to the metastatic nature of NPC. [Cancer Res 2007;67(5):1970–8]

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