Resistance of Sézary cells to TNF-α-induced apoptosis is mediated in part by a loss of TNFR1 and a high level of the IER3 expression.
Resistance of Sézary cells to TNF-α-induced apoptosis is mediated in part by a loss of TNFR1 and a high level of the IER3 expression.
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DOI：
10.1111/j.1600-0625.2012.01452.x
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发表时间：
2012-04
影响因子：
3.6
通讯作者：
Geskin LJ
中科院分区：
文献类型：
--
作者：
Akilov OE;Wu MX;Ustyugova IV;Falo LD Jr;Geskin LJ
细胞凋亡程序执行失败是促进肿瘤发生的关键步骤之一和常见机制。立即早期反应基因3（IER 3）已被证明在几种癌症中上调。IER 3是一种应激诱导基因，其上调导致活性氧（ROS）产生减少，保护恶性细胞免于凋亡。我们观察到Szary综合征（SzS）患者的恶性淋巴细胞对促凋亡剂量的肿瘤坏死因子-α（TNF-α）具有抵抗性。本研究的目的是研究IER 3在这种耐药机制中的作用。使用CD 4和CD 26磁珠从SzS患者和健康对照的外周血中阴性选择CD 4 + CD 26 −淋巴细胞，并分析TNFR 1、TNFR 2、IER 3表达和ROS产生对凋亡剂量的TNF-α的反应。IER 3表达水平较高的Sézary细胞对TNF-α保持了活力。IER 3上调与恶性细胞上细胞内ROS水平降低和TNFR 1表达降低相关。靶向IER 3可能对SzS患者未来治疗策略的发展感兴趣。
Failure to execute an apoptotic program is one of the critical steps and a common mechanism promoting tumorogenesis. Immediate early responsive gene 3 (IER3) has been shown to be upregulated in several cancers. IER3 is a stress induced gene, which upregulation leads to reduction in production of reactive oxygen species (ROS) protecting malignant cells from apoptosis. We observed that malignant lymphocytes from patients with Sézary syndrome (SzS) were resistant to pro-apoptotic dose of tumor necrosis factor-α (TNF-α). The aim of this study was to investigate the role of IER3 in the mechanism of such resistance. CD4+ CD26− lymphocytes from the peripheral blood of patients with SzS and healthy controls were negatively selected using CD4 and CD26 magnetic beads and analyzed for expression of TNFR1, TNFR2, IER3 expression, and ROS production in response to TNF-α at an apoptotic dose. Sézary cells with a higher level of IER3 expression retained their viability to TNF-α. IER3 upregulation correlated with a decrease level of intracellular ROS and low TNFR1 expression on malignant cells. Targeting IER3 could be of interest for the development of future therapeutic strategies for patients with SzS.
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