Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Mol Cancer. 2010 Feb 9;9:32. 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.
约 30-50%的霍奇金淋巴瘤（HL）中存在 EBV，但 EBV 感染对临床结局的影响尚不清楚。所有 EBV 感染的细胞中都存在 EBV 编码的小 RNA（EBERs），但其功能仍知之甚少。
EBER1 转染至两种 HL 细胞系 KMH2 和 L428 中，并用微阵列筛选 EBER1 诱导的变化。我们发现 EBER1 抑制了 HL 细胞系中 p21cip1/waf1 的转录。此外，p21cip1/waf1 转录的阳性调节剂，如 p53、EGR1 和 STAT1，减少。EBER1+HL 细胞系中 p21cip1/waf1 的抑制与对组蛋白去乙酰化酶抑制剂或蛋白酶体抑制剂的耐药性增加有关，这些药物通过增加 p21cip1/waf1 水平而导致细胞凋亡。在活检标本中，EBV+HLs 中 p21cip1/waf1 和活性 caspase 3 的表达均较弱。临床研究中，EBV+HLs 中 p21cip1/waf1 的抑制与 2 年无病生存率较差相关（EBV+HLs 为 45%，而 EBV-HL 为 77%，p=0.002）。
尽管潜在机制尚相对不清楚，但 EBER1 通过下调 p53、EGR1 和 STAT1 抑制 p21cip1/waf1 的转录并阻止细胞凋亡。EBER1 的抗凋亡活性可能在挽救 Reed-Sternberg 细胞免于药物诱导的凋亡以及 EBV+HLs 的临床行为中很重要。
