Research

EBV-positive Hodgkin lymphoma is associated with suppression of p21^cip1/waf1 and a worse prognosis

Ting-Yun Liu¹ , Shang-Ju Wu² , Mi-Hsin Huang¹ , Fei-Yun Lo¹ , Mong-Hsun Tsai³ , Ching-Hwa Tsai⁴ , Su-Ming Hsu¹ and Chung-Wu Lin¹

¹  Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, No.1, Jen-Ai Road, Taipei 100, Taiwan

²  Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, No.1, Jen-Ai Road, Taipei 100, Taiwan

³  Graduate Institute of Biotechnology, College of Bioresources and Agriculture, National Taiwan University, 4F., No.81, Changsing St., Taipei 106, Taiwan

⁴  Graduate Institute of Microbiology, National Taiwan University Hospital, National Taiwan University College of Medicine, No.1, Jen-Ai Road, Taipei 100, Taiwan

author email corresponding author email

Molecular Cancer 2010, 9:32doi:10.1186/1476-4598-9-32

Published:	9 February 2010

Abstract

Background

About 30-50% of Hodgkin lymphomas (HLs) harbor the Epstein-Barr virus (EBV), but the impact of EBV infection on clinical outcomes has been unclear. EBV-encoded small RNAs (EBERs) are presented in all EBV-infected cells, but their functions are still less understood.

Results

EBER1 was transfected into two HL cell lines, KMH2 and L428, and microarrays were used to screen for EBER1-induced changes. We found that EBER1 suppressed p21^cip1/waf1 transcription in HL cell lines. In addition, positive regulators of p21^cip1/waf1 transcription, such as p53, EGR1, and STAT1, were decreased. Suppression of p21^cip1/waf1 in the EBER1⁺ HL cell lines was associated with increased resistance to histone deacetylase inhibitors or proteasome inhibitors, drugs known to cause apoptosis by increasing p21^cip1/waf1 levels. On biopsy specimens, EBV⁺ HLs had weaker expression of both p21^cip1/waf1 and active caspase 3. Clinically, suppression of p21^cip1/waf1 in EBV⁺ HLs was associated with a worse 2-year disease-free survival rate (45% for EBV⁺ HLs vs. 77% for EBV^- HLs, p = 0.002).

Conclusion

Although the underlying mechanisms are still relatively unclear, EBER1 inhibits p21^cip1/waf1 transcription and prevents apoptosis through down-regulation of p53, EGR1, and STAT1. The anti-apoptotic activity of EBER1 may be important in the rescue of Reed-Sternberg cells from drug-induced apoptosis and in the clinical behaviors of EBV⁺ HLs.