EBV-positive Hodgkin lymphoma is associated with suppression of p21cip1/waf1 and a worse prognosis

• Published in: Molecular cancer 2010-02, Vol.9 (1), p.32-32, Article 32
• Main Authors: Liu, Ting-Yun, Wu, Shang-Ju, Huang, Mi-Hsin, Lo, Fei-Yun, Tsai, Mong-Hsun, Tsai, Ching-Hwa, Hsu, Su-Ming, Lin, Chung-Wu
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Bioinformatics; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cloning; Colleges & universities; Cyclin D2 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Drug Resistance, Neoplasm - drug effects; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genomes; Herpesvirus 4, Human - drug effects; Herpesvirus 4, Human - physiology; Hodgkin Disease - diagnosis; Hodgkin Disease - genetics; Hodgkin Disease - pathology; Hodgkin Disease - virology; Humans; Hydroxamic Acids - pharmacology; Kinases; Leupeptins - pharmacology; Medical prognosis; Medical research; Medicine; Models, Biological; Plasmids; Prognosis; RNA, Viral - metabolism; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Transcription, Genetic - drug effects; Tumor Suppressor Protein p53 - metabolism; University colleges
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-9-32

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. 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 p21cip1/waf1 transcription in HL cell lines. In addition, positive regulators of p21cip1/waf1 transcription, such as p53, EGR1, and STAT1, were decreased. Suppression of p21cip1/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 p21cip1/waf1 levels. On biopsy specimens, EBV+ HLs had weaker expression of both p21cip1/waf1 and active caspase 3. Clinically, suppression of p21cip1/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). Although the underlying mechanisms are still relatively unclear, EBER1 inhibits p21cip1/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.