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RAGE-binding S100A8/A9 promotes the migration and invasion of human breast cancer cells through actin polymerization and epithelial–mesenchymal transition

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An Erratum to this article was published on 21 March 2016

Abstract

S100A8/A9 proteins are members of EF-hand calcium-binding proteins secreted by neutrophils and activated monocytes. S100A8/A9 has cell growth-promoting activity at low concentrations by binding to the receptor for advanced glycation end products (RAGE). In this study, we report for the first time that S100A8/A9 promoted the invasion of breast cancer cells depending on RAGE. In addition, RAGE binding to S100A8/A9 promoted the phosphorylation of LIN-11, Isl1, and MEC-3 protein domain kinase, as well as cofilin. This phosphorylation is a critical step in cofilin recycling and actin polymerization. Interestingly, RAGE binding to S100A8/A9 enhanced cell mesenchymal properties and induced epithelial–mesenchymal transition. Mechanistically, RAGE binding to S100A8/A9 stabilized Snail through the NF-κB signaling pathway. Based on these observations, RAGE expression in breast cancer cells was associated with lymph node and distant metastases in patients with invasive ductal carcinoma. Moreover, RAGE binding to S100A8/A9 promoted lung metastasis in vivo. In summary, our in vitro and in vivo results indicated that RAGE binding to S100A8/A9 played an important role in breast cancer invasion/metastasis. This study identified both RAGE and S100A8/A9 as potential anti-invasion targets for therapeutic intervention in breast cancer.

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Acknowledgments

This work was supported by the National Scientific Foundation of China (81072068), the Young and Middle-Aged Scientists Research Awards Foundation of Shandong Province (2010BSB14050 and BS2011YY060), and the Foundation of Shandong Educational Committee (J12LK03, J10LF64, and J13LK03).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. College of Nursing, Weifang Medical University, Weifang, 261053, China

    Chonggao Yin & Guohua Lu

  2. Medicine Research Center, Weifang Medical University, Weifang, 261053, China

    Hongli Li

  3. Department of Pathology, Weifang Medical University, Weifang, 261053, China

    Baogang Zhang, Yuqing Liu, Shijun Lu, Lei Sun, Yueliang Qi, Xiaolong Li & Weiyi Chen

  4. Department of Pathology, Key Clinical Specialty for Pathology of Shandong Province, Affiliated Hospital of Weifang Medical University, Weifang, 261053, China

    Baogang Zhang, Yuqing Liu, Shijun Lu, Lei Sun, Yueliang Qi, Xiaolong Li & Weiyi Chen

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  1. Chonggao Yin
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Correspondence to Baogang Zhang.

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Chonggao Yin, Hongli Li, and Baogang Zhang have contributed equally to this work.

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10549_2013_2737_MOESM1_ESM.tif

Fig. S1 Comparison of cell proliferation in breast cancer cell lines. Each data point was an average of triplicate assays. Columns, mean of triplicate measurements; Bars, standard deviation (TIFF 78 kb)

10549_2013_2737_MOESM2_ESM.tif

Fig. S2 Comparison of cell proliferation in Scr/MDA231 and SiRAGE/MDA231 cells. Each data point was an average of triplicate assays. Columns, mean of triplicate measurements; Bars, standard deviation (TIFF 78 kb)

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Yin, C., Li, H., Zhang, B. et al. RAGE-binding S100A8/A9 promotes the migration and invasion of human breast cancer cells through actin polymerization and epithelial–mesenchymal transition. Breast Cancer Res Treat 142, 297–309 (2013). https://doi.org/10.1007/s10549-013-2737-1

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