Selective Activation of Ceruloplasmin Promoter in Ovarian Tumors
Selective Activation of Ceruloplasmin Promoter in Ovarian Tumors
复制标题
卵巢肿瘤中铜蓝蛋白启动子的选择性激活
作者：
Christine M. Lee;H. Lo;R. Shao;Shao;W. Xia;D. Gershenson;M. Hung
基因治疗为癌症患者提供了一种新的治疗方法。理想情况下，由癌症特异性启动子驱动的治疗基因的表达将仅针对肿瘤，从而对正常组织产生最小的毒性。虽然卵巢癌患者需要更有效和更耐受的治疗，但我们的目标是鉴定在卵巢肿瘤中具有高活性的基因启动子，这些启动子可潜在地用于基因治疗以驱动肿瘤中治疗基因的表达。为了识别此类启动子，进行了文献检索以揭示与正常卵巢组织相比在卵巢癌中优先表达的基因。我们发现，与永生化的正常细胞相比，铜蓝蛋白启动子使卵巢癌细胞中的荧光素酶表达提高了 30 倍。此外，缺失研究表明，铜蓝蛋白启动子中的激活蛋白 1 (AP-1) 位点对于铜蓝蛋白启动子的最佳活性至关重要。铜蓝蛋白启动子活性被 c-jun 激活剂 1-O-十四酰佛波醇-13-乙酸酯显着激活，而 c-jun 抑制剂 SP600125 则相反地被抑制。一致地，铜蓝蛋白 AP-1 位点在体外和体内均被 c-jun 特异性识别。人类卵巢癌标本的免疫组织化学分析显示，c-jun 和铜蓝蛋白的表达水平之间存在直接相关性（r = 0.7，P = 0.007）。在携带SKOV3.ip1异种移植物的裸鼠中，与正常器官相比，铜蓝蛋白启动子在肿瘤中表现出显着更高的活性。总之，这些结果表明，血浆铜蓝蛋白启动子活性在卵巢癌中显着增强，因此可以用作开发卵巢癌新基因治疗策略的有前景的癌症特异性启动子。
Gene therapy provides a novel treatment approach to cancer patients. Ideally, expression of therapeutic genes driven by cancer-specific promoters would only target tumors resulting in minimal toxicity to normal tissues. While there is a need of more effective and tolerable treatments for ovarian cancer patients, we aimed to identify gene promoters with high activity in ovarian tumors that can be potentially used in gene therapy to drive the expression of a therapeutic gene in tumors. To identify such promoters, a literature search was performed to reveal genes that are preferentially expressed in ovarian cancer compared with normal ovarian tissue. We found that the ceruloplasmin promoter drove up to 30-fold higher luciferase expression in ovarian cancer cells compared with immortalized normal cells. Furthermore, deletion studies revealed an activator protein-1 (AP-1) site in the ceruloplasmin promoter to be critical for optimal ceruloplasmin promoter activity. Ceruloplasmin promoter activity was significantly activated by 1-O-tetradecanoyl phorbol-13-acetate, a c-jun activator, and conversely suppressed by SP600125, a c-jun inhibitor. Consistently, the ceruloplasmin AP-1 site was specifically recognized by c-jun both in vitro and in vivo. Immunohistochemical analyses of human ovarian cancer specimens showed a direct correlation (r = 0.7, P = 0.007) between expression levels of c-jun and ceruloplasmin. In nude mice carrying SKOV3.ip1 xenografts, the ceruloplasmin promoter demonstrated significantly higher activities in tumors compared with normal organs. Together, these results suggest that the ceruloplasmin promoter activity is significantly enhanced in ovarian cancer and therefore may be exploited as a promising cancer-specific promoter in developing new gene therapy strategies for ovarian cancer.
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影响因子：
4.7
作者：
R. Bao;M. Selvakumaran;T. C. Hamilton
通讯作者：
R. Bao;M. Selvakumaran;T. C. Hamilton
影响因子：
45.3
作者：
Bookman, MA;McGuire, WP;Ozols, RF
通讯作者：
Ozols, RF
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。
影响因子：
4.7
作者：
Tanyi,JanosL;Lapushin,Ruth;Eder,Astrid;Auersperg,Nelly;Tabassam,FazalH;Roth,JackA;Gu,Jian;Fang,Binglian;Mills,GordonB;Wolf,Judith
通讯作者：
Wolf,Judith
影响因子：
45.3
作者：
Hortobagyi, GN;Ueno, NT;Hung, MC
通讯作者：
Hung, MC