siRNA targeting the IRF2 transcription factor inhibits leukaemic cell growth.
siRNA targeting the IRF2 transcription factor inhibits leukaemic cell growth.
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DOI：
10.3892/ijo.33.1.175
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发表时间：
2008-07
影响因子：
5.2
通讯作者：
Ailyn Choo;P. Palladinetti;T. Holmes;S. Basu;S. Shen;R. Lock;T. O'Brien;G. Symonds;A. Dolnikov
中科院分区：
文献类型：
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作者：
Ailyn Choo;P. Palladinetti;T. Holmes;S. Basu;S. Shen;R. Lock;T. O'Brien;G. Symonds;A. Dolnikov
干扰素调节因子（IRF）1及其功能拮抗剂IRF 2最初被发现是调节干扰素β基因的转录因子。细胞生长的控制导致IRF 1被定义为肿瘤抑制基因，IRF 2被定义为癌基因。在临床上，大约70%的急性髓性白血病病例表现出IRF 1和/或IRF 2表达失调。我们以前的研究表明，人白血病TF-1细胞表现出IRF 1和IRF 2的异常高表达，后者可消除IRF 1的肿瘤抑制作用，使这些细胞成为IRF 2表达下调分析的理想细胞。开发了一种新的G418筛选方案，并用于鉴定靶向IRF 2的有效siRNA（siIRF 2）。在白血病TF-1细胞中使用优化的siIRF 2，IRF 2在mRNA和蛋白质水平下调约70%。表型上，这导致与G2/M期阻滞相关的生长抑制以及多倍体、分化和凋亡的诱导。与这些结果相反，siIRF 2靶向不影响正常造血干/祖细胞生长。这些结果表明IRF 2抑制作为癌症治疗方法的潜在效用。
Interferon regulatory factor (IRF) 1 and its functional antagonist IRF2 were originally discovered as transcription factors that regulate the interferon-beta gene. Control of cell growth has led to the definition of IRF1 as a tumour suppressor gene and IRF2 as an oncogene. Clinically, approximately 70% of cases of acute myeloid leukaemia demonstrate dysregulated expression of IRF1 and/or IRF2. Our previous studies have shown that human leukaemic TF-1 cells exhibit abnormally high expression of both IRF1 and IRF2, the latter acting to abrogate IRF1 tumour suppression, making these cells ideal for analysis of down-regulation of IRF2 expression. A novel G418 screening protocol was developed and used for identifying effective siRNA that targets IRF2 (siIRF2). Using optimized siIRF2 in leukaemic TF-1 cells, IRF2 was down-regulated by approximately 70% at both mRNA and protein levels. Phenotypically, this resulted in growth inhibition associated with G2/M arrest as well as induction of polyploidy, differentiation and apoptosis. In contrast to these results, siIRF2 targeting did not affect normal haematopoietic stem/progenitor cell growth. These results indicate the potential utility of IRF2 inhibition as a therapeutic approach to cancer.