Cancer-specific activation of the survivin promoter and its potential use in gene therapy
Cancer-specific activation of the survivin promoter and its potential use in gene therapy
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DOI：
10.1038/sj.cgt.7700752
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发表时间：
2004-11-01
影响因子：
6.4
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Chen, JS;Liu, JC;Hung, MC
Survivin在许多癌症中表达，但在正常成人组织中不表达，并且受转录调节。为了测试在肺癌基因治疗中使用存活素启动子诱导癌症特异性转基因表达的可行性，构建了表达由存活素启动子驱动的荧光素酶基因的载体，并在体外和体内进行了评估。我们发现生存素启动子在癌细胞系中比在正常和永生化的正常细胞系中通常更高度活化。当通过DNA：脂质体复合物静脉内递送时，存活素启动子在体内的癌症特异性比巨细胞病毒启动子高200倍以上。为了确定肺癌患者谁可能受益于基因治疗与生存素启动子，我们测量了生存素蛋白表达的手术标本的75个非小细胞肺癌和10个正常肺组织的免疫组化染色，发现生存素是表达在大多数的非小细胞肺癌测试（81%，61 75），但没有正常肺组织。生存素启动子还诱导癌细胞中突变体Bik的转基因表达，其在体外和体内抑制癌细胞的生长。这些结果表明，生存素启动子是一个癌症特异性启动子，为各种癌症，它可能是有用的癌症基因治疗。
Survivin is expressed in many cancers but not in normal adult tissues and is transcriptionally regulated. To test the feasibility of using the survivin promoter to induce cancer-specific transgene expression in lung cancer gene therapy, a vector expressing a luciferase gene driven by the survivin promoter was constructed and evaluated in vitro and in vivo. We found that the survivin promoter was generally more highly activated in cancer cell lines than in normal and immortalized normal cell lines. When delivered intravenously by DNA:liposome complexes, the survivin promoter was more than 200 times more cancer specific than the cytomegalovirus promoter in vivo. To identify lung cancer patients who may benefit from gene therapy with the survivin promoter, we measured survivin protein expression in surgical specimens of 75 non-small-cell lung cancers and 10 normal lung tissues by immunohistochemical staining and found that survivin is expressed in most of the non-small-cell lung cancers tested (81%, 61 of 75) but none of the normal lung tissues. The survivin promoter also induced transgene expression of a mutant Bik in cancer cells, which suppressed the growth of cancer cells in vitro and in vivo. These results indicate that the survivin promoter is a cancer-specific promoter for various cancers and that it may be useful in cancer gene therapy.