Kazhdan I, Long L, Montellano R, Cavazos D A, Marciniak R A
Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Cancer Gene Ther. 2006 Feb;13(2):141-9. doi: 10.1038/sj.cgt.7700867.
We studied the efficiency of the proapoptotic factor tBid, targeted to tumor cells using the promoters of the hTERT, Survivin and Muc1 genes, in killing breast cancer cells. tBid is the active fragment of the proapoptotic protein Bid and is generated in response to death receptor activation. When placed under control of a strong CMV promoter, tBid was highly efficient in killing breast cancer cells. When expression of tBid was driven by tumor-specific promoters, the magnitude of killing was significant in cell lines with high levels of promoter activity. For successful gene therapy with targeted tBid, it is therefore crucial to be able to predict promoter activity prior to selection of the therapeutic construct. To test whether gene expression could serve as a predictor, we correlated expression of Survivin, hTERT and Muc1 genes with the activity of the corresponding promoters in a panel of breast cancer cell lines. Expression of the Muc1 gene correlated well with the activity of its promoter and the resultant tumor cell killing. For the hTERT and Survivin promoters, however, promoter activity did not correlate well with the expression of the corresponding genes. The implications and possible mechanism of these discrepancies are discussed.
我们研究了利用人端粒酶逆转录酶（hTERT）、生存素（Survivin）和粘蛋白1（Muc1）基因的启动子靶向肿瘤细胞的促凋亡因子截短型Bid（tBid）在杀伤乳腺癌细胞方面的效率。tBid是促凋亡蛋白Bid的活性片段，由死亡受体激活产生。当置于强巨细胞病毒（CMV）启动子控制下时，tBid在杀伤乳腺癌细胞方面效率很高。当tBid的表达由肿瘤特异性启动子驱动时，在启动子活性高的细胞系中杀伤程度显著。因此，对于用靶向tBid进行成功的基因治疗而言，在选择治疗构建体之前能够预测启动子活性至关重要。为了测试基因表达是否可作为预测指标，我们在一组乳腺癌细胞系中将Survivin、hTERT和Muc1基因的表达与其相应启动子的活性进行了关联。Muc1基因的表达与其启动子的活性以及由此导致的肿瘤细胞杀伤密切相关。然而，对于hTERT和Survivin启动子，启动子活性与相应基因的表达相关性不佳。文中讨论了这些差异的意义和可能机制。
