Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo
Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo
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DOI：
10.1158/1078-0432.ccr-05-0148
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发表时间：
2005-09-01
影响因子：
11.5
通讯作者：
Xu, DQ
中科院分区：
文献类型：
--
作者：
Gao, LF;Zhang, L;Xu, DQ
目的：信号转导和转录激活因子3(STAT3)在多种肿瘤中被结构性激活，是前列腺癌的共同特征。因此，STAT3有望成为肿瘤治疗的分子靶点。我们应用基于DNA载体的STAT3特异性RNA干扰方法来阻断STAT3信号，并通过小鼠模型评估STAT3下调对肿瘤生长的生物学影响。实验设计：为了研究在肿瘤细胞中阻断STAT3的治疗潜力，三个小干扰RNA(siRNA；结果：在3个相同表达的siRNAs中，只有分别针对SH2结构域和卷曲线圈结构域的STAT3-3和STAT3-2能强烈抑制PC3和LNCaP细胞中STAT3的表达。针对DNA结合区的STAT3-1siRNA对STAT3的表达没有影响，提示siRNA的基因沉默效率可能依赖于STAT3mRNA的局部结构。STAT3 siRNAs下调前列腺癌细胞中抗凋亡蛋白Bcl2、细胞周期蛋白D1和c-Myc的表达，抑制STAT3及其相关基因的表达，可抑制体外培养的前列腺癌细胞和裸鼠移植瘤的生长和诱导细胞凋亡。结论：STAT3信号转导通路有望成为前列腺癌治疗的分子靶点，VEDOR为基础的Stat3siRNA可作为前列腺癌的治疗药物。
Purpose: Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a variety of cancers and it is a common feature of prostate cancer. Thus, Stat3 represents a promising molecular target for tumor therapy. We applied a DNA vector - based Stat3-specific RNA interference approach to block Stat3 signaling and to evaluate the biological consequences of Stat3 down-modulation on tumor growth using a mouse model.Experimental Design: To investigate the therapeutic potential of blocking Stat3 in cancer cells, three small interfering RNAs (siRNA; Stat3-1, Stat3-2, and Stat3-3) specific for different target sites on Stat3 mRNA were designed and used with a DNA vector-based RNA interference approach expressing short hairpin RNAs to knockdown Stat3 expression in human prostate cancer cells in vitro as well as in vivo.Results: Of the three equivalently expressed siRNAs, only Stat3-3 and Stat3-2, which target the region coding for the SH2 domain and the coiled-coil domain, respectively, strongly suppressed the expression of Stat3 in PC3 and LNCaP cells. The Stat3-1 siRNA, which targeted the DNA-binding domain, exerted no effect on Stat3 expression, indicating that the gene silencing efficiency of siRNA may be dependent on the local structure of Stat3 mRNA. The Stat3 siRNAs down-regulated the expression of Bcl-2 (an antiapoptotic protein), and cyclin D1 and c-Myc (cell growth activators) in prostate cancer cells, Inhibition of Stat3 and its related genes was accompanied by growth suppression and induction of apoptosis in cancer cells in vitro and in tumors implanted in nude mice.Conclusions: These data indicate that Stat3 signaling is a promising molecular target for prostate cancer therapy and that vedor-based Stat3siRNA may be useful as a therapeutic agent for treatment of prostate cancer.