Epstein-Barr Virus-Encoded Small RNAs (EBERs) Are Present in Fractions Related to Exosomes Released by EBV-Transformed Cells

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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Cell Surface Alteration in Epstein-Barr Virus-Transformed Cells From Patients With Extreme Insulin Resistance

Diabetes ◽

10.2337/diab.39.8.924 ◽

1990 ◽

Vol 39 (8) ◽

pp. 924-927 ◽

Cited By ~ 1

Author(s):

D. L. Gorden ◽

A. Robert ◽

V. Y. Moncada ◽

S. I. Taylor ◽

J. Muhlhauser ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Surface ◽

Epstein Barr Virus ◽

Transformed Cells ◽

Barr Virus ◽

Surface Alteration ◽

Extreme Insulin Resistance ◽

Epstein Barr

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EAP, a highly conserved cellular protein associated with Epstein-Barr virus small RNAs (EBERs).

The EMBO Journal ◽

10.1002/j.1460-2075.1991.tb07968.x ◽

1991 ◽

Vol 10 (2) ◽

pp. 459-466 ◽

Cited By ~ 67

Author(s):

D. P. Toczyski ◽

J. A. Steitz

Keyword(s):

Small Rnas ◽

Epstein Barr Virus ◽

Cellular Protein ◽

Barr Virus ◽

Epstein Barr

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Epstein-Barr Virus Small RNAs Potentiate Tumorigenicity of Burkitt Lymphoma Cells Independently of an Effect on Apoptosis

Journal of Virology ◽

10.1128/jvi.74.21.10223-10228.2000 ◽

2000 ◽

Vol 74 (21) ◽

pp. 10223-10228 ◽

Cited By ~ 70

Author(s):

Ingrid K. Ruf ◽

Paul W. Rhyne ◽

Chunying Yang ◽

John L. Cleveland ◽

Jeffery T. Sample

Keyword(s):

Cell Survival ◽

Cell Line ◽

Burkitt Lymphoma ◽

Small Rnas ◽

Epstein Barr Virus ◽

Wild Type ◽

Barr Virus ◽

Tumorigenic Potential ◽

Epstein Barr ◽

Dependent Mechanism

ABSTRACT The tumorigenic potential of the Burkitt lymphoma (BL) cell line Akata is dependent on the restricted latency program of Epstein-Barr virus (EBV) that is characteristically maintained in BL tumors. Within these cells, EBV-mediated inhibition of apoptosis correlates with an up-regulation of BCL-2 levels in concert with a down-regulation in c-MYC expression that occurs under growth-limiting conditions. Here we addressed whether EBV's effects on apoptosis and tumorigenicity are mediated by the EBV small RNAs EBER-1 and EBER-2. Stable expression of the EBERs in EBV-negative Akata BL cells, at levels comparable to those in EBV-positive cells, significantly enhanced the tumorigenic potential of EBV-negative BL cells in SCID mice, but did not fully restore tumorigenicity relative to EBV-positive Akata cells. Furthermore, wild-type or greater levels of EBER expression in EBV-negative Akata cells did not promote BL cell survival. These data therefore suggest that EBV can contribute to BL through at least two avenues: an EBER-dependent mechanism that enhances tumorigenic potential independent of a direct effect on apoptosis, and a second mechanism, mediated by an as-yet-unidentified EBV gene(s), that offsets the proapoptotic consequences of deregulated c-MYC in BL.

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