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


CONCLUSIONS
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.
Liu
Ting-Yun
TY
Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Wu
Shang-Ju
SJ
Huang
Mi-Hsin
MH
Lo
Fei-Yun
FY
Tsai
Mong-Hsun
MH
Tsai
Ching-Hwa
CH
Hsu
Su-Ming
SM
Lin
Chung-Wu
CW
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D056742:Cyclin D2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000502:physiology*; D006689:Hodgkin Disease / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008954:Models, Biological; D011379:Prognosis; D012367:RNA, Viral / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C099537:Epstein-Barr virus encoded RNA 1; D006877:Hydroxamic Acids; D007976:Leupeptins; D012367:RNA, Viral; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016159:Tumor Suppressor Protein p53; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C012589:trichostatin A