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Journal of Virology, February 1999, p. 1286-1292, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Epstein-Barr Virus Promotes Epithelial Cell Growth in the Absence of EBNA2 and LMP1 Expression

Jun Nishikawa,1,2 Shosuke Imai,2 Takanori Oda,2 Toshichika Kojima,3 Kiwamu Okita,1 and Kenzo Takada2,*

First Department of Internal Medicine, Yamaguchi University School of Medicine, Ube 755-8505,1 Department of Virology, Cancer Institute, Hokkaido University School of Medicine, Sapporo 060-8638,2 and Department of Gastroenterology, Jichi Medical School, Minamikawachi 329-0400,3 Japan

Received 31 August 1998/Accepted 19 October 1998

We attempted to infect primary gastric epithelia (PGE) with recombinant Epstein-Barr virus (EBV) carrying a selectable marker that made it possible to select EBV-infected cells. Cells dually positive for EBV-determined nuclear antigen (EBNA) and cytokeratin were detected in 3 of 21 primary cultures after 3 days of EBV inoculation. From one culture, EBV-infected cell clones were repeatedly obtained at a frequency of 3 to 5 cell clones per 106 cells. EBV-infected clones had enhanced population doubling and grew to attain a highly increased saturation density, together with acquisition of marked anchorage independence. The infected clones retained the ultrastructural morphology characteristic of gastric mucosal epithelium and have been growing stably for more than 18 months (corresponding to at least 300 generations) so far, in clear contrast to the parental PGE cells, which ceased growth after 60 generations. The p53 gene of the parental PGE cells was found to be overexpressed, perhaps thereby conferring the basal potential for long-term survival in vitro. Moreover, EBV infection accelerated, to a significant extent, the growth rate and agar clonability of NU-GC-3 cells, an established EBV-negative but EBV-susceptible human gastric carcinoma cell line. Both EBV-converted PGE and NU-GC-3 clones, like EBV-positive gastric carcinoma biopsy specimens, expressed a restricted set of EBV latent infection genes characterized by the absence of EBNA2 and latent membrane protein 1 (LMP1) expression. These results indicate that EBV infection causes a transformed phenotype on PGE in the setting of possible unregulated cell cycling and renders even established gastric carcinoma cells more malignant via a limited spectrum of viral latent-gene expression. This study may reflect an in vivo scenario illustrating multiphasic involvement of EBV in carcinogenesis of gastric or other epithelial cancers.

* Corresponding author. Mailing address: Department of Virology, Cancer Institute, Hokkaido University School of Medicine, N15 W7, Kita-ku, Sapporo 060-8638, Japan. Phone: 81-11-706-5071. Fax: 81-11-717-1128. E-mail: kentaka{at}med.hokudai.ac.jp.

Journal of Virology, February 1999, p. 1286-1292, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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