carbobenzoxy-leucyl-leucyl-norvalinal and Hodgkin-Disease

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.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cyclin D2; Cyclin-Dependent Kinase Inhibitor p21; Drug Resistance, Neoplasm; Early Growth Response Protein 1; Gene Expression Regulation, Neoplastic; Herpesvirus 4, Human; Hodgkin Disease; Humans; Hydroxamic Acids; Leupeptins; Models, Biological; Prognosis; RNA, Viral; STAT1 Transcription Factor; Transcription, Genetic; Tumor Suppressor Protein p53