6-OH-BDE-47 promotes human lung cancer cells epithelial mesenchymal transition via the AKT/Snail signal pathway

Abstract Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been detected in the various human tissues. The OH-PBDEs are suggested to be stronger endocrine-disrupting compounds than PBDEs, therefore the toxicological effects of OH-PBDEs had received lots of attention. However, there is no study about the carcinogenic effect of OH-PBDEs and their estrogen potencies on the tumorigenesis and development of cancer. In the present study, we found that 6-hydroxy-2,2′,4′,4′-tetrabromodiphenyl ether (6-OH-BDE-47), the most abundant OH-PBDE congeners in human serum, promoted the in vitro migration of lung cancer A549 and H358 cells by induction of epithelial to mesenchymal transition (EMT). This was confirmed by that 6-OH-BDE-47 significantly down regulated the expression of epithelial markers E-cadherin (E-Cad) and zona occludin-1 (ZO-1) while up regulated the mesenchymal markers vimentin (Vim) and N-cadherin (N-Cad). 6-OH-BDE-47 up regulated the protein while not mRNA levels of Snail, which was the key transcription factor of EMT. Silencing of Snail by use of siRNA attenuated the 6-OH-BDE-47 induced EMT. This suggested that the stabilization of Snail was essential for 6-OH-BDE-47 induced EMT. Further, the treatment of 6-OH-BDE-47 increased the phosphorylation of AKT and ERK in A549 cells. Only PI3K/AKT inhibitor (LY294002), but not ERK inhibitor (PD98059), completely blocked the 6-OH-BDE-47 induced up regulation of Snail and down regulation of E-Cad, suggesting that PI3K/AKT pathway is important for 6-OH-BDE-47-mediated Snail stabilization and EMT in A549 cells. Generally, our results revealed for the first time that 6-OH-BDE-47 promoted the EMT of lung cancer cells via AKT/Snail signals. This suggested that more attention should be paid to the effects of OH-PBDEs on tumorigenesis and development of lung cancer.