Use of the XRCC2 promoter for in vivo cancer diagnosis and therapy.
Use of the XRCC2 promoter for in vivo cancer diagnosis and therapy.
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使用 XRCC2 启动子进行体内癌症诊断和治疗。
DOI：
10.1038/s41419-018-0453-9
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发表时间：
2018-04-01
影响因子：
9
通讯作者：
Mao Z
中科院分区：
文献类型：
--
作者：
Chen Y;Li Z;Xu Z;Tang H;Guo W;Sun X;Zhang W;Zhang J;Wan X;Jiang Y;Mao Z
同源重组（HR）途径是癌症治疗的有希望的靶点，因为它在肿瘤中经常上调。一种这样的策略是用癌症特异性的、高活性的HR基因启动子（包括RAD 51和RAD 51 C）靶向肿瘤。然而，启动子大小和递送方法限制了其潜在的临床应用。在这里，我们鉴定了XRCC 2的~2.1 kb启动子，类似于~6.5 kb RAD 51启动子，在癌细胞中也被过度激活。我们发现，XRCC 2表达在几乎所有类型的癌症中都上调，其程度与RAD 51相当，但远高于RAD 51 C。进一步的研究表明，XRCC 2启动子在癌细胞系中被过度激活，由XRCC 2启动子驱动的白喉毒素A（DTA）基因特异性地消除癌细胞。此外，创建了含有驱动萤火虫荧光素酶或DTA的XRCC 2启动子的慢病毒载体，并将其应用于皮下HeLa异种移植小鼠。我们证明了pXRCC 2-荧光素酶慢病毒是体内癌症可视化的有效工具。最重要的是，与对照组相比，pXRCC 2-DTA慢病毒显著抑制HeLa异种移植物的生长。总之，我们的研究结果强烈表明，病毒介导的交付构建在XRCC 2启动子上的肿瘤诊断和治疗具有很大的潜力。
The homologous recombination (HR) pathway is a promising target for cancer therapy as it is frequently upregulated in tumors. One such strategy is to target tumors with cancer-specific, hyperactive promoters of HR genes including RAD51 and RAD51C. However, the promoter size and the delivery method have limited its potential clinical applications. Here we identified the ~2.1 kb promoter of XRCC2, similar to ~6.5 kb RAD51 promoter, as also hyperactivated in cancer cells. We found that XRCC2 expression is upregulated in nearly all types of cancers, to a degree comparable to RAD51 while much higher than RAD51C. Further study demonstrated that XRCC2 promoter is hyperactivated in cancer cell lines, and diphtheria toxin A (DTA) gene driven by XRCC2 promoter specifically eliminates cancer cells. Moreover, lentiviral vectors containing XRCC2 promoter driving firefly luciferase or DTA were created and applied to subcutaneous HeLa xenograft mice. We demonstrated that the pXRCC2-luciferase lentivirus is an effective tool for in vivo cancer visualization. Most importantly, pXRCC2-DTA lentivirus significantly inhibited the growth of HeLa xenografts in comparison to the control group. In summary, our results strongly indicate that virus-mediated delivery of constructs built upon the XRCC2 promoter holds great potential for tumor diagnosis and therapy.
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