Journal of Biological Chemistry
Volume 289, Issue 32, 8 August 2014, Pages 22151-22160
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Signal Transduction
Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells*

https://doi.org/10.1074/jbc.M114.556126Get rights and content
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Inflammation and inflammatory mediators are inextricably linked with epithelial-mesenchymal transition (EMT) through complex pathways in the tumor microenvironment. However, the mechanism by which inflammatory mediators, such as the lipid inflammatory mediators, eicosanoids, contribute to EMT is largely unknown. In the present study we observed that BLT2, leukotriene B4 receptor-2, is markedly up-regulated by oncogenic Ras and promotes EMT in response to transforming growth factor-β (TGF-β) in mammary epithelial cells. Blockade of BLT2 by the BLT2 inhibitor LY255283 or by siRNA reduced EMT induced by Ras in the presence of TGF-β. In addition, stimulation of BLT2 by the addition of a BLT2 ligand, such as leukotriene B4, restored EMT in the presence of TGF-β in human immortalized mammary epithelial MCF-10A cells. We further searched BLT2 downstream components and identified reactive oxygen species and nuclear factor κB as critical components that contribute to EMT. Taken together, these results demonstrate for the first time that a BLT2-linked inflammatory pathway contributes to EMT. This provides valuable insight into the mechanism of EMT in mammary epithelial cells. In addition, considering the implications of EMT with the stemness of cancer cells, our finding may contribute to a better understanding of tumor progression.

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*

This work was supported by Bio and Medical Technology Development Program Grant 2012M3A9C5048709, Basic Science Research Program Grant 2012R1A2A2A01044526 through the National Research Foundation funded by the Ministry of Science, Information, and Communication Technologies (ICT) and Future Planning, Republic of Korea, and the National Research and Development Program for Cancer Control Grant 1220020, Ministry for Health and Welfare, Republic of Korea.

2

The abbreviations used are:

    EMT

    epithelial-mesenchymal transition

    LTB4

    leukotriene B4

    ROS

    reactive oxygen species

    Nox

    NADPH oxidase.