Dual mechanism of deltaEF1 expression regulated by bone morphogenetic protein-6 in breast cancer.
Dual mechanism of deltaEF1 expression regulated by bone morphogenetic protein-6 in breast cancer.
复制标题
DOI：
10.1016/j.biocel.2008.08.030
复制
发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Shuang Yang;Jun Du;Zhaoqi Wang;Ji-dong Yan;W. Yuan;Jie Zhang;T. Zhu
中科院分区：
文献类型：
--
作者：
Shuang Yang;Jun Du;Zhaoqi Wang;Ji-dong Yan;W. Yuan;Jie Zhang;T. Zhu
乳腺癌的转移性已经得到了很好的认识，但乳腺癌细胞获得其侵袭性的机制尚未明确阐明。我们前期的研究表明，BMP-6通过抑制δ EF 1恢复乳腺癌中E-cadherin介导的EMT。然而，BMP-6调节δ EF 1表达的机制仍不清楚。在这项研究中，我们证实了BMP-6在抑制MDA-MB-231迁移中的重要作用，通过降低δ EF 1表达，随后减轻δ EF 1介导的侵袭。在MDA-MB-231和MCF-7细胞和临床肿瘤标本中观察到的BMP-6/miR-192和δ EF 1表达的负相关性支持BMP-6通过δ EF 1调节的抑制作用。此外，BMP-6处理或miR-192转染降低了δ EF 1 3′-UTR-luc的报告活性，验证了δ EF 1是miR-192的靶点。同时，我们还发现BMP-6是人δ EF 1启动子的有效转录抑制因子。该启动子上AP-1结合位点的突变消除了BMP-6诱导的δ EF 1反式阻遏。通过RNAi消除BMP-6表达导致δ EF 1启动子活性显著增加。我们的研究提供了BMP-6调节乳腺癌细胞中δ EF 1表达的双重机制的新发现，涉及AP-1介导的转录抑制和miR介导的翻译抑制之间的交叉对话。
The metastatic nature of breast cancer has been well recognized, yet the mechanisms through which breast cancer cells acquire their invasive properties have not been clearly elucidated. Our previous study indicates that BMP-6 restores E-cadherin-mediated EMT through repressing δEF1 in breast cancer. However, the mechanism by which BMP-6 regulates δEF1 expression remains unclear. In this study, we confirmed the significant role of BMP-6 in inhibiting MDA-MB-231 migration through decreasing δEF1 expression which subsequently relieves δEF1-mediated invasion. The inhibitory effect of BMP-6 through δEF1 regulation was supported by an inverse correlation of BMP-6/miR-192 and δEF1 expressions observed in both MDA-MB-231 and MCF-7 cells and clinical tumor specimens. Moreover, BMP-6 treatment or miR-192 transfection decreased the reporter activity of the δEF1 3′-UTR-luc, validating that δEF1 is a target of miR-192. Meanwhile, we also found that BMP-6 acted as a potent transcriptional repressor of the human δEF1 promoter. Mutation of the AP-1 binding site on this promoter abolished BMP-6-induced transrepression of δEF1. Depletion of BMP-6 expression by RNAi resulted in a significant increase in the promoter activity of δEF1. Our study has provided novel findings of a dual mechanism for BMP-6-regulated δEF1 expression in breast cancer cells, involving cross-talks between AP-1-mediated transcriptional repression and miRs-mediated translational inhibition.