Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells.
Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells.
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DOI：
10.18632/oncotarget.14120
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发表时间：
2017-01-24
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影响因子：
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通讯作者：
Nadal D
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文献类型：
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作者：
Mordasini V;Ueda S;Aslandogmus R;Berger C;Gysin C;Hühn D;Sartori AA;Bernasconi M;Nadal D
以b细胞为主要靶点的eb病毒（EBV）对免疫功能低下的宿主的原发性感染与EBV相关肿瘤的风险增加有关。原发性感染后的早期事件与潜在的b细胞转化的研究很少。由于EBV的物种特异性阻碍了实验动物的建模，因此我们使用从扁桃体分离的b细胞体外模拟原代感染，扁桃体是EBV的进入门户。越来越多的证据表明，宿主DNA损伤反应（DDR）可以影响和受EBV感染的影响。因此，我们用EBV-B95.8接种扁桃体b细胞（tbc），并在接种后的前96小时内观察细胞增殖和DDR。我们首次发现EBV感染TBCs后可诱导48-96小时的过度增殖，其特征是共济失调毛细血管扩张和rad3相关（ATR）和检查点激酶-1 （Chk1）的激活。抑制Chk1不影响b细胞转化，而特异性抑制ATR则显著降低EBV的转化效率。我们的研究结果表明ATR的激活是eb病毒诱导的b细胞转化的关键。因此，靶向ATR/Chk1与EBV之间的相互作用可能为EBV相关恶性肿瘤的治疗提供新的选择。
Primary infection of the immunocompromised host with the oncovirus Epstein-Barr virus (EBV) that targets mainly B-cells is associated with an increased risk for EBV-associated tumors. The early events subsequent to primary infection with potential for B-cell transformation are poorly studied. Here, we modeled in vitro the primary infection by using B-cells isolated from tonsils, the portal of entry of EBV, since species specificity of EBV hampers modeling in experimental animals. Increasing evidence indicates that the host DNA damage response (DDR) can influence and be influenced by EBV infection. Thus, we inoculated tonsillar B-cells (TBCs) with EBV-B95.8 and investigated cell proliferation and the DDR during the first 96 hours thereafter. We identified for the first time that EBV infection of TBCs induces a period of hyperproliferation 48-96 hours post infection characterized by the activation of ataxia telangiectasia and Rad3-releated (ATR) and checkpoint kinase-1 (Chk1). Whereas inhibition of Chk1 did not affect B-cell transformation, the specific inhibition of ATR robustly decreased the transformation efficiency of EBV. Our results suggest that activation of ATR is key for EBV-induced B-cell transformation. Thus, targeting the interaction between ATR/Chk1 and EBV could offer new options for the treatment of EBV-associated malignancies.