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Phosphorylated ezrin is associated with EBV latent membrane protein 1 in nasopharyngeal carcinoma and induces cell migration

Oncogene volume 28, pages 1725–1735 (2009)Cite this article

Abstract

Tumor metastasis is a complex phenomenon that is the culmination of effects of numerous cellular factors. We have shown that the Epstein–Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1), is capable of inducing a wide range of such factors in cell culture, expression of which is also elevated in the LMP1-expressing tumor, nasopharyngeal carcinoma (NPC), a highly invasive neoplasm. Recently, the membrane crosslinker protein, ezrin, has been implicated in tumor cell metastasis and malignant progression. In this study, we evaluated the possible role of LMP1 and ezrin in the pathophysiology of NPC. We show that C-terminal phosphorylation of ezrin is increased by the expression of LMP1 in nasopharyngeal (NP) cells through a protein kinase C (PKC) pathway. LMP1 enhances the organization of a ternary complex of CD44, ezrin and F-actin, which is a prerequisite for ezrin phosphorylation. In NPC tissues, the expression of phosphoezrin and LMP1 is directly correlated. Silencing of endogenously expressed ezrin suppresses LMP1-induced cell motility and invasiveness. Moreover, the inhibition of ezrin phosphorylation by PKC inhibitor suppresses migration and invasion of NP cells. These data show that the phosphorylation of ezrin and its recruitment to the cell membrane linked to F-actin and CD44 is a process required for LMP1-stimulated cell motility and invasion of NP cells.

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Acknowledgements

We thank Sai Wah Tsao and Erik K Flemington for the NP69SV40T cell line and the Ad-AH cell line, respectively. We thank Drs Yojiro Kotake and Yuki Okada for helpful advice. This work was supported by NCI (CA 19014) (JSP) and the Nakayama Foundation for Human Science (Tokyo, Japan) (KE).

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    K Endo, J Shackleford & J S Pagano

  2. Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan

    K Endo, S Kondo, T Horikawa, N Kitagawa, T Yoshizaki & M Furukawa

  3. Division of Pathology, Kanazawa University Hospital, Kanazawa, Japan

    Y Zen

  4. Departments of Medicine and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA

    J S Pagano

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  1. K Endo
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Correspondence to J S Pagano.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Endo, K., Kondo, S., Shackleford, J. et al. Phosphorylated ezrin is associated with EBV latent membrane protein 1 in nasopharyngeal carcinoma and induces cell migration. Oncogene 28, 1725–1735 (2009). https://doi.org/10.1038/onc.2009.20

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