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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetic reprogramming of tumor cells by zinc finger transcription factors
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Genetic reprogramming of tumor cells by zinc finger transcription factors

机译：锌指转录因子对肿瘤细胞的遗传重编程

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摘要

Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drug-resistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires coregulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By coregulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes.
机译：癌症是由于DNA中遗传变异的积累导致异常基因转录而引起的。表达谱研究已将全基因组表达特征与恶性肿瘤相关联。然而，阐明特定癌细胞表型中基因的贡献和协同作用的功能分析仍然是一个巨大的障碍。在这里，我们描述了一种替代的遗传方法，用于通过使用锌指人工转录因子（ATF）库和肿瘤细胞的功能筛选作为遗传可塑性和克隆选择的来源，来鉴定参与肿瘤进展的基因。我们分离了六锌指转录激活因子（TF 20-VP，包含VP64激活因子域的TF20），其作用是将药物敏感性，低侵袭性和非转移性细胞系重编程为具有耐药性，高侵袭性的细胞系和转移表型。表达TF 20-VP的细胞的差异表达谱，以及随后在体外和动物模型中进行的功能研究均表明，侵袭和转移需要多种靶基因的协同调节。值得注意的是，E48抗原与头颈部癌的无转移生存能力差有关，被确定为TF 20-VP的特定靶标。我们已经显示了通过E48表达对肿瘤细胞行为的表型调节，包括增强的体外细胞迁移和体内的肿瘤细胞传播。这项研究证明了使用ATF来识别在肿瘤进展过程中协作的基因组。通过整合多个靶标，ATF可以用作主要的遗传开关，以重新编程和调节复杂的肿瘤表型。

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