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. 1999 Dec;73(12):9827-31.
doi: 10.1128/JVI.73.12.9827-9831.1999.

Oncogenic role of Epstein-Barr virus-encoded RNAs in Burkitt's lymphoma cell line Akata

J Komano  1 , S Maruo, K Kurozumi, T Oda, K Takada
Affiliations

Oncogenic role of Epstein-Barr virus-encoded RNAs in Burkitt's lymphoma cell line Akata

J Komano et al. J Virol. 1999 Dec.

Abstract

Our previous reports indicated that Epstein-Barr virus (EBV) contributes to the malignant phenotype and resistance to apoptosis in Burkitt's lymphoma (BL) cell line Akata (N. Shimizu, A. Tanabe-Tochikura, Y. Kuroiwa, and K. Takada, J. Virol. 68:6069-6073, 1994; J. Komano, M. Sugiura, and K. Takada, J. Virol. 72:9150-9156, 1998). Here we report that the EBV-encoded small RNAs (EBERs) are responsible for these phenotypes. Transfection of the EBER genes into EBV-negative Akata clones restored the capacity for growth in soft agar, tumorigenicity in SCID mice, resistance to apoptotic inducers, and upregulated expression of bcl-2 oncoprotein that were originally retained in parental EBV-positive Akata cells and lost in EBV-negative subclones. This is the first report which provides evidence that virus-encoded RNAs (EBERs) have oncogenic functions in BL cells.

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Figures

FIG. 1
FIG. 1
Relative EBER expression in EK- and EKS10-transfected Akata cells compared with EBV-reinfected Akata cells. For each EBER transfectant derived from different EBV-negative clones, more than 50 cell clones were examined for EBER expression, and 4 to 6 clones with the highest levels of EBER expression were chosen for further studies. Representative results are shown. Four EBER-transfected cell clones from an EBV-negative Akata cell clone were mixed and subjected to quantitative assays for EBER. (A) Schematic drawing of the EcoRI K fragment of Akata EBV DNA (left) and relative EBER expression in EK-transfected cells (right). (B) Schematic drawing of EKS10 (left) and relative EBER expression in EKS10-transfected cells (right). avr, average.
FIG. 2
FIG. 2
Colony production in soft agar for neoR-transfected, EK-transfected, EKS10-transfected, and EBV-reinfected cells. The individual panels show independent experiments with different EBV-negative Akata cell clones. Each dot represents the number of visible colonies emerging per 104 cells. Horizontal bars represent the mean values for each group. The differences between neoR-transfected and EKS10-transfected cell clones were significant (P, <0.01), as determined by the Mann-Whitney U test.
FIG. 3
FIG. 3
Histological examination of tumors derived from EKS10-transfected Akata cells in SCID mice. Adjacent sections from paraffin-embedded blocks were stained by hematoxylin-eosin or subjected to an in situ hybridization study. Typical lymphoma histology was observed (left panel; magnification, ×400). The EBER-1 in situ hybridization study revealed that almost all the tumor cells were positive for EBER-1 expression (middle panel; magnification, ×400). Dark signals representing the presence of EBER-1 transcripts were specifically present in the nuclei of tumor cells. A negative control for the EBER-1 in situ hybridization study is also shown (right panel; magnification, ×400).
FIG. 4
FIG. 4
Resistance to apoptosis of neoR-transfected, EK-transfected, EKS10-transfected, and EBV-reinfected cells tested with CHX (A), glucocorticoid (Gluc) (B), and hypoxic stress (C). The bars show the means ± standard deviations for six clones. The data are typical results from three independent experiments. As determined by a t test analysis, the differences between mean values for neoR- and EKS10-transfected cells were significant at P values of <0.01 (CHX), <0.05 (Gluc), and <0.001 (hypoxic stress).
FIG. 5
FIG. 5
Expression of bcl-2 protein in neoR-transfected, EKS10-transfected, and EBV-reinfected (rEBV) cells derived from two independent EBV-negative Akata cell clones. The data are typical results from several experiments.
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