Interleukin enhancer-binding factor 3 promotes breast tumor progression by regulating sustained urokinase-type plasminogen activator expression.
Interleukin enhancer-binding factor 3 promotes breast tumor progression by regulating sustained urokinase-type plasminogen activator expression.
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DOI：
10.1038/onc.2012.414
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发表时间：
2013-08-22
期刊：
影响因子：
8
通讯作者：
Huang, S.
中科院分区：
文献类型：
--
作者：
Hu, Q.;Lu, Y-Y;Noh, H.;Hong, S.;Dong, Z.;Ding, H-F;Su, S-B;Huang, S.
持续尿激酶型纤溶酶原激活剂（uPA）的表达检测在侵袭性乳腺肿瘤。虽然uPA可以通过多种细胞外刺激瞬时上调，但持续但非瞬时上调的uPA表达有助于乳腺癌侵袭/转移。不幸的是，如何持续uPA表达实现浸润性/转移性乳腺癌细胞是未知的。在这里，我们表明，持续和瞬时上调uPA表达的不同机制进行调节。使用一系列靶向转录因子的siRNAs，我们发现白细胞介素增强子结合因子3（ILF 3）是持续uPA表达所需的。两个独立的机制介导ILF 3的作用。第一种是ILF 3通过与uPA启动子-1，004 ~-1，000核苷酸的CTGTT序列结合激活uPA转录;第二种是ILF 3抑制uPA mRNA靶向pri-miRNA的加工。ILF 3的敲低导致体外细胞生长/迁移/侵袭和体内乳腺肿瘤发展的显著减少。重要的是，免疫组化显示，细胞核ILF 3，而不是细胞质ILF 3染色与升高的uPA水平和较高级别的人乳腺肿瘤标本相关。ILF 3的核定位突出了ILF 3作为转录激活剂和pri-miRNA加工阻断剂在持续uPA表达中的作用。总之，本研究表明，ILF 3通过调节持续的uPA表达促进乳腺致瘤性。
Sustained urokinase-type plasminogen activator (uPA) expression is detected in aggressive breast tumors. Although uPA can be transiently upregulated by diverse extracellular stimuli, sustained, but not transiently-upregulated uPA expression contributes to breast cancer invasion/metastasis. Unfortunately, how sustained uPA expression is achieved in invasive/metastatic breast cancer cells is unknown. Here, we show that sustained and transiently-upregulated uPA expression are regulated by distinct mechanisms. Using a collection of transcription factor-targeted siRNAs, we discovered that interleukin enhancer binding factor 3 (ILF3) is required for sustained uPA expression. Two discrete mechanisms mediate ILF3 action. The first is that ILF3 activates uPA transcription by binding to the CTGTT sequence in the nucleotides -1,004~-1,000 of the uPA promoter; the second is that ILF3 inhibits the processing of uPA mRNA-targeting pri-miRNAs. Knockdown of ILF3 led to significant reduction in in vitro cell growth/migration/invasion and in vivo breast tumor development. Importantly, immunohistochemistry showed that nuclear ILF3, but not cytoplasmic ILF3 staining correlates with elevated uPA level and higher grades of human breast tumor specimens. Nuclear localization of ILF3 highlights the role of ILF3 in sustained uPA expression as a transcription activator and pri-miRNA processing blocker. In conclusion, this study shows that ILF3 promotes breast tumorigenicity by regulating sustained uPA expression.
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