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Interleukin enhancer-binding factor 3 promotes breast tumor progression by regulating sustained urokinase-type plasminogen activator expression

Oncogene volume 32, pages 3933–3943 (2013)Cite this article

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Abstract

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 small-interfering RNAs, 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 −1004∼−1000 of the uPA promoter; the second is that ILF3 inhibits the processing of uPA mRNA-targeting primary microRNAs (pri-miRNAs). Knockdown of ILF3 led to significant reduction in in vitro cell growth/migration/invasion and in vivo breast tumor development. Importantly, immunohistochemistry (IHC) 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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Acknowledgements

This work was supported by funding from NIH CA093926 (SH), NSF of China Fund 81 073 134 (SBS) and Shanghai Eastern Scholar Fund (SH). We would like to thank Dr Michael Mathews for providing ILF3 splicing isoform constructs.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA, USA

    Q Hu, H Noh, S Hong & S Huang

  2. Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Y-Y Lu, S-B Su & S Huang

  3. Department of Cellular Biology and Anatomy, Georgia Health Sciences University, Augusta, GA, USA

    Z Dong

  4. Department of Pathology, Medical College of Georgia, Augusta, GA, USA

    H-F Ding

  5. Cancer Center, Georgia Health Sciences University, Augusta, GA, USA

    H-F Ding & S Huang

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Correspondence to S Huang.

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Hu, Q., Lu, YY., Noh, H. et al. Interleukin enhancer-binding factor 3 promotes breast tumor progression by regulating sustained urokinase-type plasminogen activator expression. Oncogene 32, 3933–3943 (2013). https://doi.org/10.1038/onc.2012.414

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