BMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cells.
BMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cells.
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DOI：
10.1186/1471-2407-7-211
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发表时间：
2007-11-13
期刊：
影响因子：
3.8
通讯作者：
Zhu, Tianhui
中科院分区：
文献类型：
--
作者：
Yang, Shuang;Du, Jun;Wang, Zhaoqi;Yuan, Wei;Qiao, Yuhuan;Zhang, Ming;Zhang, Jie;Gao, Songyuan;Yin, Jian;Sun, Baocun;Zhu, Tianhui
骨形态发生蛋白-6（BMP-6）在许多发育过程中起重要作用。近年来的研究表明，BMP-6与肿瘤的分化和转移密切相关。应用RT-PCR方法检测MCF-7、MDA-MB-231乳腺癌细胞及16例乳腺癌标本中BMP-6、E-cadherin和δ EF 1的mRNA表达。免疫印迹法检测δ EF 1过表达和干扰后MDA-MB-231细胞中δ EF 1的表达。荧光素酶法检测rhBMP-6或δ EF 1对MDA-MB-231细胞中E-cadherin启动子转录活性的影响。采用定量CHIP法检测MDA-MB-231细胞中δ EF 1与E-cadherin近端启动子的直接结合。MCF-7乳腺癌细胞是一种表达高水平BMP-6和E-cadherin的ER+细胞系，其δ EF 1转录水平非常低。相比之下，ER-细胞系MDA-MB-231细胞具有显著降低的BMP-6和E-钙粘蛋白mRNA水平，表明BMP-6/E-钙粘蛋白与δ EF 1之间呈负相关。为了确定在人类肿瘤中是否存在相同的关系，我们检查了来自人类受试者的乳腺癌组织样本。在16例乳腺癌标本中，ER阳性者（4/8例）和ER阴性者（7/8例）的BMP-6/E-cadherin与δ EF 1呈负相关。BMP-6可抑制δ EF 1的转录，从而上调E-cadherin mRNA的表达。这与我们对E-钙粘蛋白启动子的分析一致，表明BMP-6是一种有效的转录激活剂。有趣的是，δ EF 1的异位表达能够阻断BMP-6诱导的E-钙粘蛋白的反式激活，而RNA干扰介导的乳腺癌细胞中内源性δ EF 1的下调消除了BMP-6对E-钙粘蛋白的反式激活。BMP-6除了下调δ EF 1的表达外，还将δ EF 1从E-钙粘蛋白启动子上物理性地移除，从而允许激活E-钙粘蛋白转录。我们的结论是，δ EF 1的抑制在介导BMP-6诱导的乳腺癌细胞中E-cadherin的转录激活中起关键作用。与较高水平的δ EF 1表达与乳腺癌细胞更具侵袭性表型相关的事实一致，我们的集体数据表明δ EF 1可能是BMP-6恢复E-钙粘蛋白介导的细胞间粘附并防止乳腺癌转移的开关。
Bone morphogenetic protein-6 (BMP-6) is critically involved in many developmental processes. Recent studies indicate that BMP-6 is closely related to tumor differentiation and metastasis. Quantitative RT-PCR was used to determine the expression of BMP-6, E-cadherin, and δEF1 at the mRNA level in MCF-7 and MDA-MB-231 breast cancer cells, as well as in 16 breast cancer specimens. Immunoblot analysis was used to measure the expression of δEF1 at the protein level in δEF1-overexpressing and δEF1-interfered MDA-MB-231 cells. Luciferase assay was used to determine the rhBMP-6 or δEF1 driven transcriptional activity of the E-cadherin promoter in MDA-MB-231 cells. Quantitative CHIP assay was used to detect the direct association of δEF1 with the E-cadherin proximal promoter in MDA-MB-231 cells. MCF-7 breast cancer cells, an ER+ cell line that expressed high levels of BMP-6 and E-cadherin exhibited very low levels of δEF1 transcript. In contrast, MDA-MB-231 cells, an ER- cell line had significantly reduced BMP-6 and E-cadherin mRNA levels, suggesting an inverse correlation between BMP-6/E-cadherin and δEF1. To determine if the same relationship exists in human tumors, we examined tissue samples of breast cancer from human subjects. In 16 breast cancer specimens, the inverse correlation between BMP-6/E-cadherin and δEF1 was observed in both ER+ cases (4 of 8 cases) and ER- cases (7 of 8 cases). Further, we found that BMP-6 inhibited δEF1 transcription, resulting in an up-regulation of E-cadherin mRNA expression. This is consistent with our analysis of the E-cadherin promoter demonstrating that BMP-6 was a potent transcriptional activator. Interestingly, ectopic expression of δEF1 was able to block BMP-6-induced transactivation of E-cadherin, whereas RNA interference-mediated down-regulation of endogenous δEF1 in breast cancer cells abolished E-cadherin transactivation by BMP-6. In addition to down-regulating the expression of δEF1, BMP-6 also physically dislodged δEF1 from E-cadherin promoter to allow the activation of E-cadherin transcription. We conclude that repression of δEF1 plays a key role in mediating BMP-6-induced transcriptional activation of E-cadherin in breast cancer cells. Consistent with the fact that higher level of δEF1 expression is associated with more invasive phenotype of breast cancer cells, our collective data suggests that δEF1 is likely the switch through which BMP-6 restores E-cadherin-mediated cell-to-cell adhesion and prevents breast cancer metastasis.
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影响因子：
7.8
作者：
Gitelman, S E;Kobrin, M S;Ye, J Q;Lopez, A R;Lee, A;Derynck, R
通讯作者：
Derynck, R
影响因子：
11.2
作者：
Deckers, M;van Dinther, M;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
4.1
作者：
Dillner, NB;Sanders, MM
通讯作者：
Sanders, MM
DOI：
10.1073/pnas.91.12.5528
发表时间：
1994-06-07
影响因子：
11.1
作者：
DROZDOFF, V;WALL, NA;PLEDGER, WJ
通讯作者：
PLEDGER, WJ
影响因子：
2.5
作者：
Hatsell, S;Rowlands, T;Cowin, P
通讯作者：
Cowin, P