Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers
Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers
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DOI：
10.4161/cbt.5.7.2893
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发表时间：
2006-07-01
影响因子：
3.6
通讯作者：
Yang, An-Gang
中科院分区：
文献类型：
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作者：
Li, Qing-Xia;Zhao, Jing;Yang, An-Gang
对细胞凋亡的抗性增加是许多肿瘤细胞的标志。Survivin是IAP家族蛋白的一员，在多种肿瘤中表达，在保护细胞免于凋亡中起重要作用。在这里，我们表明，载体为基础的小干扰RNA（siRNA）稳定敲低生存素在几种癌细胞系的表达，导致增加凋亡率在不同的促凋亡刺激，如阿霉素或TNF-α。凋亡易感性依赖于不同水平的生存素表达。稳定转染的细胞形态异常，细胞生长受到抑制，自发凋亡增加，细胞周期受阻。此外，在存活素阳性肿瘤的裸鼠异种移植物中，表达存活素靶向siRNA的细胞表现出减少的肿瘤形成和减少的血管生成。这些研究的结果：（1）提供了通过siRNA使存活素的细胞内沉默使人类肿瘤细胞对凋亡敏感的直接证据;（2）将存活素定义为癌症治疗的有希望的分子靶点;和（3）表明存活素靶向siRNA用于治疗人类肿瘤的潜在适用性，可能与化疗组合。
Increased resistance to apoptosis is a hallmark of many tumor cells. Survivin, a member of IAP family protein, is expressed in many human cancers and plays an important role in protecting cells from apoptosis. Here we show that vector-based small interfering RNAs (siRNA) stably knockdown survivin expression in several cancer cell lines, leading to increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin or TNF-alpha. The apoptotic susceptibility was dependent on divergent levels of survivin expression. The stable transfectants exhibited abnormal morphology, suppressed cell growth, enhanced spontaneous apoptosis and cell cycle hindrance. Furthermore, in nude mice xenografts of survivin-positive tumors, cells expressing survivin-targeted siRNAs exhibited decreased tumor formation and reduced angiogenesis. Results from these studies: (1) provide direct evidence that intracellular silencing of survivin by siRNA sensitizes human tumor cells to apoptosis; (2) define survivin as a promising molecular target for cancer therapy; and (3) suggest the potential applicability of survivin-targeted siRNA for treating human tumors, probably in combination with chemotherapy.