Identification of tissue- and cancer-selective promoters for the introduction of genes into human ovarian cancer cells.
Identification of tissue- and cancer-selective promoters for the introduction of genes into human ovarian cancer cells.
复制标题
鉴定用于将基因引入人卵巢癌细胞的组织和癌症选择性启动子。
DOI：
10.1006/gyno.2002.6644
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发表时间：
2002
影响因子：
4.7
通讯作者：
Wolf,Judith
中科院分区：
文献类型：
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作者：
Tanyi,JanosL;Lapushin,Ruth;Eder,Astrid;Auersperg,Nelly;Tabassam,FazalH;Roth,JackA;Gu,Jian;Fang,Binglian;Mills,GordonB;Wolf,Judith
上皮性肿瘤基因治疗的一个潜在局限性是缺乏组织或肿瘤特异性的治疗。基因治疗的肿瘤选择性表达可以避免有害的副作用并提高治疗的功效。本研究的目的是评估四种不同的潜在基因治疗启动子的组织和肿瘤特异性，以确定它们在上皮性卵巢癌的组织特异性基因治疗中的有用性。（hESE 1，SLP1，OSP 1）和一种潜在的肿瘤选择性（hTERT）将启动子置于荧光素酶构建体的上游以测定在多种正常和恶性细胞系中的相对活性。瞬时转染和荧光素酶测定进行了12上皮卵巢（3 SV 40 T抗原转染正常和9恶性）和8个对照细胞株。ResultsLuciferase测定显示，hTERT启动子提出了最高的肿瘤选择性。hESE 1和SLP 1启动子显示出强的上皮细胞选择性（hESE 1，16/17; SLP 1，15/17），而OSP 1（11/17）启动子显示出较低的上皮细胞选择性。在基因治疗的潜在启动子中，hTERT启动子在大多数肿瘤细胞系中表现出最强的转录活性。结论hTERT启动子具有较高的肿瘤选择性，可能成为单载体基因治疗的理想启动子。利用多种上皮细胞特异性启动子可能会导致更具有组织选择性的基因治疗方法。使用启动子的组合可以防止由于在可以组成性表达hTERT的非上皮干细胞中表达而引起的潜在问题。
ObjectiveOne potential limitation of gene therapy for epithelial tumors is the lack of tissue or tumor specificity of treatment. Tumor-selective expression of gene therapies may avoid deleterious side effects and improve the efficacy of the treatment. The aim of this study was to evaluate the tissue and tumor specificity of four different potential gene therapy promoters, to determine their usefulness in tissue-specific gene therapy of epithelial ovarian carcinomas.MethodsThree potential epithelial cell-selective (hESE1, SLP1, OSP1) and one potential tumor-selective (hTERT) promoter were placed upstream of a luciferase construct to determine relative activity in a wide variety of normal and malignant cell lines. Transient transfection and luciferase assays were carried out in 12 epithelial ovarian (3 SV40 T antigen-transfected normal and 9 malignant) and 8 control cell lines.ResultsLuciferase assays revealed that the hTERT promoter presented the highest tumor selectivity. hESE1 and SLP1 promoters showed strong epithelial cell selectivity (hESE1, 16/17; SLP1, 15/17), with the OSP1 (11/17) promoter exhibiting lower epithelial selectivity. Of the potential promoters for gene therapy, hTERT promoter exhibited the strongest transcriptional activity in most of the tumor cell lines. None of the promoters exhibited strict ovarian epithelium selectivity.ConclusionThe hTERT promoter may be an optimal promoter for a univector gene therapy approach based on its high tumor selectivity. Utilization of multiple epithelial cell-specific promoters may result in a more tissue-selective gene therapy approach. Using a combination of promoters may prevent potential problems due to expression in nonepithelial stem cells that may constitutively express hTERT.