Stat3 as a molecular target in RNA interference-based treatment of oral squamous cell carcinoma
Stat3 as a molecular target in RNA interference-based treatment of oral squamous cell carcinoma
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DOI：
10.3892/or_00000085
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发表时间：
2008-10-01
期刊：
影响因子：
4.2
通讯作者：
Hamakawa, Hiroyuki
中科院分区：
文献类型：
--
作者：
Klosek, Sebastian Krystian;Nakashiro, Koh-Ichi;Hamakawa, Hiroyuki
在许多人类恶性肿瘤中观察到信号换能器和转录激活子3 （Stat3）的组成性激活。使用序列特异性RNA干扰（RNAi）方法来关闭Stat3的表达，可能会阻止癌症的生长。在本研究中，我们旨在鉴定合成的Stat3特异性小干扰RNA （siRNA）的最有效序列（Stat3-siRNA）以及Stat3抑制对口腔鳞状细胞癌细胞生长的影响。筛选10种已知序列的设计sirna，在1和10 nM的工作浓度下获得最佳RNAi效果。10 nM sirna的Stat3表达减少幅度为21% ~ 67%，1 nM sirna的Stat3表达减少幅度为13% ~ 73%。与GFP-siRNA对照相比，筛选的10种sirna中有3种将Stat3的表达降低到较低水平。在10 nM的浓度下观察到一些sirna对干扰素的反应。然而，在1 nM时，干扰素应答基因（OAS1、OAS2、MX1和ISFG3 γ）的mRNA水平保持不变。与其他stat3 - sirna和GFP-siRNA相比，使用三种有效的stat3 - sirna可强烈抑制GFP-SAS、HSC-3、HSC-4和KB细胞的生长。此外，Stat3激活转录的基因的mRNA水平被显著抑制。这些结果表明，使用siRNA靶向Stat3可能是治疗口腔鳞状细胞癌的一种有效方法。
Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been observed in many human malignancies. Using the sequence-specific RNA interference (RNAi) method to switch off Stat3 expression, it may be possible to arrest cancer growth. In this study, we aimed to identify the most effective sequence of a synthetic small interfering RNA (siRNA) specific for Stat3 (Stat3-siRNA) and the effect of Stat3 suppression on the growth of oral squamous cell carcinoma cells. Ten designed siRNAs with known sequences were screened for the best RNAi effect at the working concentrations of 1 and 10 nM. The range of reduction of Stat3 expression varied from 21 to 67% for 10 nM siRNAs, and from 13 to 73% for 1 nM siRNAs. Three out of the 10 screened siRNAs reduced Stat3 expression to lower levels compared with the GFP-siRNA control. The interferon response of some siRNAs was observed at a concentration of 10 nM. However, at I nM, the mRNA levels of interferon response genes (OAS1, OAS2, MX1 and ISFG3 gamma) remained unchanged. The growth of GFP-SAS, HSC-3, HSC-4 and KB cells was strongly inhibited by the use of three effective Stat3-siRNAs in comparison with other Stat3-siRNAs and GFP-siRNA. Moreover, the mRNA levels of genes for which transcription is activated by Stat3 were markedly suppressed. These results suggest that targeting Stat3 using, siRNA may constitute a useful approach for the treatment of oral squamous cell carcinoma.