Kim Joo Hyun, Kim Won Seog, Hong Jung Yong, Ryu Kung Ju, Kim Seok Jin, Park Chaehwa
Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Oncotarget. 2017 Jan 17;8(3):5361-5370. doi: 10.18632/oncotarget.14243.
Epstein-Barr virus (EBV)-encoded nuclear antigen, EBNA2, expressed in EBV-infected B lymphocytes is critical for lymphoblastoid cell growth. Microarray profiling and cytokine array screening revealed that EBNA2 is associated with upregulation of the chemokines CCL3 and CCL4 in lymphoma cells. Depletion or inactivation of CCL3 or CCL4 sensitized DLBCL cells to doxorubicin. Our results indicate that EBV influences cell survival via an autocrine mechanism whereby EBNA2 increases CCL3 and CCL4, which in turn activate the Btk and NF-κB pathways, contributing to doxorubicin resistance of B lymphoma cells. Western blot data further confirmed that CCL3 and CCL4 direct activation of Btk and NF-κB. Based on these findings, we propose that a pathway involving EBNA2/Btk/NF-κB/CCL3/CCL4 plays a key role in doxorubicin resistance, and therefore, inhibition of specific components of this pathway may sensitize lymphoma cells to doxorubicin. Evaluation of the relationship between CCL3 expression and EBV infection revealed high CCL3 levels in EBV-positive patients. Our data collectively suggest that doxorubicin treatment for EBNA2-positive DLBCL cells may be effectively complemented with a NF-κB or Btk inhibitor. Moreover, evaluation of the CCL3 and CCL4 levels may be helpful for selecting DLBCL patients likely to benefit from doxorubicin treatment in combination with the velcade or ibrutinib.
在EB病毒（EBV）感染的B淋巴细胞中表达的EBV编码核抗原EBNA2对淋巴母细胞生长至关重要。微阵列分析和细胞因子阵列筛选显示，EBNA2与淋巴瘤细胞中趋化因子CCL3和CCL4的上调相关。CCL3或CCL4的缺失或失活使弥漫性大B细胞淋巴瘤（DLBCL）细胞对阿霉素敏感。我们的结果表明，EBV通过自分泌机制影响细胞存活，即EBNA2增加CCL3和CCL4，进而激活Btk和NF-κB通路，导致B淋巴瘤细胞对阿霉素耐药。蛋白质免疫印迹数据进一步证实CCL3和CCL4直接激活Btk和NF-κB。基于这些发现，我们提出涉及EBNA2/Btk/NF-κB/CCL3/CCL4的通路在阿霉素耐药中起关键作用，因此，抑制该通路的特定成分可能使淋巴瘤细胞对阿霉素敏感。对CCL3表达与EBV感染之间关系的评估显示，EBV阳性患者的CCL3水平较高。我们的数据共同表明，对EBNA2阳性的DLBCL细胞进行阿霉素治疗时，可有效地辅以NF-κB或Btk抑制剂。此外，评估CCL3和CCL4水平可能有助于选择可能从阿霉素与万珂或依鲁替尼联合治疗中获益的DLBCL患者。
