AP-2α and AP-2γ regulate tumor progression via specific genetic programs
AP-2α and AP-2γ regulate tumor progression via specific genetic programs
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DOI：
10.1096/fj.08-106492
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Taverna, Daniela
中科院分区：
文献类型：
--
作者：
Orso, Francesca;Penna, Elisa;Taverna, Daniela
肿瘤形成和进展过程中发生的事件与胚胎形态发生的某些步骤有相似之处。AP-2蛋白家族由五种不同的转录因子(α、β、γ、Delta和epsilon)组成，在胚胎发育中发挥相关作用，相应基因敲除小鼠的表型证明了这一点。在这里，我们表明AP-2α和AP-2伽马蛋白在肿瘤发生中起重要作用。通过RNA干扰(RNAi)下调肿瘤细胞中AP-2的表达，可以促进肿瘤生长，减少化疗诱导的细胞死亡，并减少肿瘤的迁移和侵袭。AP-2的过度表达挽救了这些生物调控中的大部分。我们观察到，异种移植生长的增加主要是由于高度促进了肿瘤细胞的增殖和减少了天然免疫细胞的募集。此外，我们还发现，迁移障碍至少在一定程度上是由分泌因素介导的。为了确定与肿瘤发生有关的遗传程序，我们对AP-2α基因敲除细胞进行了全基因组微阵列分析，观察到AP-2α调控与细胞周期、细胞死亡、黏附和迁移相关的特定基因。特别是，我们发现ESDN、Ereg和CXCL2在AP-2控制的迁移中发挥了主要作用，因为这些基因中的任何一个都会严重改变迁移。
The events occurring during tumor formation and progression display similarities to some of the steps in embryonic morphogenesis. The family of AP-2 proteins consists of five different transcription factors ( alpha,beta,gamma,delta, and epsilon) that play relevant roles in embryonic development, as demonstrated by the phenotypes of the corresponding knockout mice. Here, we show that AP-2 alpha and AP-2 gamma proteins play an essential role in tumorigenesis. Down-modulation of AP-2 expression in tumor cells by RNA interference (RNAi) led to enhanced tumor growth and reduced chemotherapy-induced cell death, as well as migration and invasion. Most of these biological modulations were rescued by AP-2 overexpression. We observed that increased xeno-transplant growth was mostly due to highly enhanced proliferation of the tumor cells together with reduced innate immune cell recruitment. Moreover, we showed that migration impairment was mediated, at least in part, by secreted factors. To identify the genetic programs involved in tumorigenesis, we performed whole genome microarray analysis of AP-2 alpha knockdown cells and observed that AP-2 alpha regulates specific genes involved in cell cycle, cell death, adhesion, and migration. In particular, we showed that ESDN, EREG, and CXCL2 play a major role in AP-2 controlled migration, as ablation of any of these genes severely altered migration.