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Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth

Oncogene volume 19, pages 1764–1771 (2000)Cite this article

Abstract

The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has a significant role in initiating EBV-associated lymphoproliferative disease and EBV-related malignancies. In view of clinical features related to the type of EBV latency, LMP1 may influence invasiveness of EBV associated tumors categorized as types II and III as represented on nasopharyngeal carcinoma (NPC). To screen for genes associated with invasion of epithelial cells transformed by LMP1, Madin-Darby canine kidney (MDCK) epithelial cells were transformed by LMP1. Stable transfection of a LMP1 gene into MDCK cells induced morphological change from cobblestone to a long spindle-shape, reduced cell-cell adhesion and caused high cell motility. Parental MDCK cells, which form spherical cysts in three-dimensional collagen gel matrix, form branching tubules following exposure to hepatocyte growth factor (HGF). MDCK cells transformed by LMP1 showed invasive growth to form branching tubules into collagen gel without HGF-treatment. mRNA differential display and Northern hybridization identified plasminogen activator inhibitor-1 (PAI-1), urokinase type plasminogen activator (uPA) and ets1 as genes upregulated during transformation by LMP1. Expression of a dominant negative type of Ets1 in LMP1-transformed cells downregulated uPA expression and cell motility. Deletion of LMP1 cytoplasmic carboxy-terminal activating region 1 (CTAR1) domain abolished transformation, but a deletion mutant lacking CTAR2 domain still retained transforming and uPA-inducing ability. Expression of Ets1 was immunolocalized in tumor cells of NPC tissue which frequently express LMP1. Taken together, it is suggested that LMP1 induces expression of Ets1 which may contribute to invasion of NPC by stimulating cell motility and uPA expression.

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Acknowledgements

We thank Dr EW Thompson for critical reading of the manuscript, Dr N Raab-Traub for expression plasmids for truncated LMP1, and Dr LA Young for the monoclonal antibody against LMP1. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, and Culture of Japan and by a grant from NOVARTIS Foundation (Japan) for the Promotion of Science.

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Authors and Affiliations

  1. Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-0934, Japan

    Kwang-Rok Kim, Tomokazu Yoshizaki, Hisashi Miyamori, Kazuki Hasegawa, Shizuko Harada & Hiroshi Sato

  2. Department of Otolaryngology, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-0934, Japan

    Tomokazu Yoshizaki, Toshiyuki Horikawa & Mitsuru Furukawa

  3. Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Shirogane-dai, 108, Minato-ku, Tokyo, Japan

    Motoharu Seiki

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Kim, KR., Yoshizaki, T., Miyamori, H. et al. Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth. Oncogene 19, 1764–1771 (2000). https://doi.org/10.1038/sj.onc.1203502

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