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The YB-1/EZH2/amphiregulin signaling axis mediates LPA-induced breast cancer cell invasion

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Abstract

Lysophosphatidic acid (LPA) has been known to induce epithelial-mesenchymal transition (EMT) to stimulate cancer cell invasion, and resveratrol (3,5,4′-trans-trihydroxystilbene; REV) suppresses the invasion and metastasis of various cancers. The current study aimed to identify the underlying mechanism by which LPA aggravates breast cancer cell invasion and the reversal of this phenomenon. Immunoblotting and quantitative RT-PCR analysis revealed that LPA induces amphiregulin (AREG) expression. Silencing of Y-box binding protein 1 (YB-1) or enhancer of zeste homolog 2 (EZH2) expression efficiently inhibited LPA-induced AREG expression. In addition, transfection of the cells with YB-1 siRNA abrogated LPA-induced EZH2 and AREG expression, leading to attenuation of breast cancer cell invasion. Furthermore, we observed that both REV and 5-fluorouracil (5-Fu) significantly reduce LPA-induced YB-1 phosphorylation and subsequent breast cancer invasion. Importantly, combined treatment of REV with 5-Fu showed more significant inhibition of LPA-induced breast cancer invasion compared to single treatment. Therefore, our data demonstrate that the YB-1/EZH2 signaling axis mediates LPA-induced AREG expression and breast cancer cell invasion and its inhibition by REV and 5-Fu, providing potential therapeutic targets and inhibition of breast cancer.

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Acknowledgements

This study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [NRF-2017R1E1A1A01074091, 2016R1D1A1B04930418, 2017R1A2B4007361].

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  1. Kyung Hwa Cho and Bo Young Jeong have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Konyang University, Myunggok Medical Building, 158 Gwanjeodong-ro, Seo-gu, Daejeon, 35365, Republic of Korea

    Kyung Hwa Cho, Bo Young Jeong, Chang Gyo Park & Hoi Young Lee

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  1. Kyung Hwa Cho
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  2. Bo Young Jeong
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Correspondence to Chang Gyo Park or Hoi Young Lee.

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Cho, K.H., Jeong, B.Y., Park, C.G. et al. The YB-1/EZH2/amphiregulin signaling axis mediates LPA-induced breast cancer cell invasion. Arch. Pharm. Res. 42, 519–530 (2019). https://doi.org/10.1007/s12272-019-01149-6

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