Unraveling the Role of FOXQ1 in Colorectal Cancer Metastasis
Unraveling the Role of FOXQ1 in Colorectal Cancer Metastasis
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DOI：
10.1158/1541-7786.mcr-13-0024
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发表时间：
2013-09-01
影响因子：
5.2
通讯作者：
Allgayer, Heike
中科院分区：
文献类型：
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作者：
Abba, Mohammed;Patil, Nitin;Allgayer, Heike
恶性细胞的转化、侵袭和转移依赖于基因表达的协调重组。这些重编程事件的支架中的一个主要组成部分是其中上皮细胞失去细胞间连接和极性以采用更能动的间充质表型，这在很大程度上由主要由发育转录因子组成的稳健的转录机制支持。这项研究表明，翼螺旋转录因子FOXQ1，有助于这一重新布线过程，部分通过直接调节TWIST 1的转录，TWIST 1本身是转移的关键介质，转录调节参与上皮间质转化的重要分子的表达。FOXQ1的强制表达和RNA介导的沉默分别导致TWIST 1的mRNA和蛋白水平的增强和抑制。FOXQ1增强了TWIST 1的报告活性，并直接与其启动子相互作用。此外，FOXQ1表达增强导致结肠直肠癌细胞系迁移和侵袭增加，而敲除研究显示相反的效果。此外，使用体内鸡绒毛尿囊膜转移测定模型，FOXQ1显著增强远处转移，对肿瘤生长的影响最小。(C)2013年AACR。
Malignant cell transformation, invasion, and metastasis are dependent on the coordinated rewiring of gene expression. A major component in the scaffold of these reprogramming events is one in which epithelial cells lose intercellular connections and polarity to adopt a more motile mesenchymal phenotype, which is largely supported by a robust transcriptional machinery consisting mostly of developmental transcription factors. This study demonstrates that the winged helix transcription factor, FOXQ1, contributes to this rewiring process, in part by directly modulating the transcription of TWIST1, itself a key mediator of metastasis that transcriptionally regulates the expression of important molecules involved in epithelial-to-mesenchymal transition. Forced expression and RNA-mediated silencing of FOXQ1 led to enhanced and suppressed mRNA and protein levels of TWIST1, respectively. Mechanistically, FOXQ1 enhanced the reporter activity of TWIST1 and directly interacted with its promoter. Furthermore, enhanced expression of FOXQ1 resulted in increased migration and invasion in colorectal cancer cell lines, whereas knockdown studies showed the opposite effect. Moreover, using the in vivo chicken chorioallantoic membrane metastasis assay model, FOXQ1 significantly enhanced distant metastasis with minimal effects on tumor growth. (C) 2013 AACR.