Transcriptional silencing of ETS-1 efficiently suppresses angiogenesis of pancreatic cancer
Transcriptional silencing of ETS-1 efficiently suppresses angiogenesis of pancreatic cancer
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DOI：
10.1038/cgt.2008.65
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发表时间：
2009-02-01
影响因子：
6.4
通讯作者：
Horii, A.
中科院分区：
文献类型：
--
作者：
Lefter, L. P.;Dima, S.;Horii, A.
在这项研究中，我们提出了这样的假设，即转录抑制成红细胞增多症病毒E26癌基因同源物1（ETS-1）是一种有效的治疗胰腺癌的方法，通过调查ETS-1抑制在人胰腺癌细胞的影响。我们通过使用仅编码野生型ETS-1（ETS-1显性阴性，ETS-1-DN）的DNA结合结构域的腺病毒载体来实现这一点。ETS-1-DN通过竞争其与DNA的结合来降低ETS-1的结合。腺病毒介导的ETS-1-DN（腺病毒ETS-1-DN构建体，AdETS-1-DN）转移到胰腺癌细胞系中并不影响其体外增殖率，但显著抑制其在裸鼠体内的生长。此外，为了测试ETS-1-DN在体内的功效，我们将AdETS-1-DN注射到在裸鼠中生长的已建立的人胰腺癌中。与盐水注射相比，这种治疗显著减小了肿瘤大小，没有任何可检测的副作用。小鼠异种移植物中的微血管密度在ETS-1下调的肿瘤中显示出显著较低的值。此外，ETS-1-DN在胰腺癌细胞中的表达导致尿激酶型纤溶酶原激活物（u-PA）和金属蛋白酶-1（MMP-1）表达下调。综上所述，这些数据表明ETS-1的转录失活能够显著影响胰腺癌的血管生成和生长。这种作用可能部分是由于MMP-1和u-PA表达下调。我们的研究结果表明ETS-1-DN是胰腺癌抗血管生成基因治疗的一个有希望的候选者。
In this study, we addressed the hypothesis that transcriptional suppression of erythroblastosis virus E26 oncogene homolog 1 (ETS-1) is an efficient therapeutic approach to pancreatic adenocarcinoma by investigating the effect of ETS-1 suppression in human pancreatic cancer cells. We accomplished this by using an adenoviral vector encoding only the DNA-binding domain of wild-type ETS-1 (ETS-1 dominant negative, ETS-1-DN). ETS-1-DN decreases ETS-1-binding by competing for its binding to DNA. Adenoviral-mediated transfer of ETS-1-DN (adenoviral ETS-1-DN construct, AdETS-1-DN) into pancreatic tumor cell lines did not affect their proliferation rate in vitro but did significantly inhibit their in vivo growth in nude mice. Furthermore, to test the efficacy of ETS-1-DN in vivo, we injected the AdETS-1-DN into established human pancreatic adenocarcinomas grown in nude mice. This treatment significantly reduced tumor size as compared to saline injection, without any detectable side effects. Microvessel density in mouse xenografts displayed significantly lower values in tumors in which ETS-1 was downregulated. In addition, expression of the ETS-1-DN in the pancreatic cancer cells resulted in downregulation of urokinase-type plasminogen activator (u-PA) and metalloproteinase-1 (MMP-1) expression. Taken together, these data suggest that transcriptional inactivation of ETS-1 is able to significantly affect angiogenesis and growth of pancreatic cancer. This effect may be due in part to downregulation of MMP-1 and u-PA expression. Our results suggest that ETS-1-DN is a promising candidate for antiangiogenic gene therapy in pancreatic cancer.