Tumor-specific gene expression using the survivin promoter is further increased by hypoxia
Tumor-specific gene expression using the survivin promoter is further increased by hypoxia
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DOI：
10.1038/sj.gt.3302280
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发表时间：
2004-08-01
期刊：
影响因子：
5.1
通讯作者：
Wood, WC
中科院分区：
文献类型：
--
作者：
Yang, L;Cao, Z;Wood, WC
越来越多的证据表明，凋亡抑制蛋白（IAP）生存素，在人类癌细胞中表达，但在大多数正常成人组织中不存在。在这里，我们研究了使用生存素启动子（Sur-P）指导治疗性表达的促凋亡基因，特别是在人类肿瘤细胞的可行性。首先，我们证明了该启动子在人类肿瘤细胞中具有高度活性，但在正常细胞中没有。第二，我们发现肿瘤细胞中的Sur-P活性被缺氧上调。第三，为了进一步增强该启动子在缺氧条件下的活性，我们在其50区域中添加了来自血管内皮生长因子基因启动子的缺氧响应元件（HRE），并表明这种组合导致缺氧肿瘤细胞中基因表达水平的进一步增加。最后，我们证明了该启动子表达的自催化逆转caspase-3基因特异性诱导人肿瘤细胞凋亡，但在正常细胞中不诱导凋亡。这些发现支持使用启动子Sur-P或嵌合HRE-Sur-P来产生用于癌症基因治疗的新型载体。
Increasing evidence indicates that survivin, an inhibitor of apoptosis protein (IAP), is expressed in human cancer cells but is absent from most normal adult tissues. Here, we examined the feasibility of using a survivin promoter (Sur-P) to direct therapeutic expression of a proapoptotic gene specifically in human tumor cells. First, we demonstrated that this promoter was highly active in human tumor cells but not in normal cells. Second, we found that Sur-P activity was upregulated by hypoxia in tumor cells. Third, to further enhance this promoter's activity under hypoxia, we added a hypoxia-responsive element (HRE) from the vascular endothelial growth factor gene promoter in its 50 region, and showed that this combination resulted in a further increase in the level of gene expression in hypoxic tumor cells. Finally, we demonstrated that expression of an autocatalytic reverse caspase-3 gene by this promoter specifically induced apoptotic cell death in human tumor cells but not in normal cells. These findings support the use of promoters Sur-P or chimeric HRE-Sur-P for generating novel vectors for cancer gene therapy.