Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells

• DOI: 10.1074/jbc.m114.556126
• Publication Date: 2014-07-03T07:52:03Z
• Authors: Hyunju Kim; Jung-A Choi; Jae-Hong Kim
• Keywords: 0301 basic medicine; Epithelial-Mesenchymal Transition; NF-kappa B; Receptors, Leukotriene B4; NADPH Oxidases; Tetrazoles; Breast Neoplasms; Cell Line; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; Transforming Growth Factor beta; NADPH Oxidase 1; Humans; Female; RNA, Small Interfering; Mammary Glands, Human; Reactive Oxygen Species; 10. No inequality; Signal Transduction

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.