BMP-6 inhibits the metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression
BMP-6 inhibits the metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression
复制标题
BMP-6通过调节MMP-1表达抑制MDA-MB-231乳腺癌细胞转移
DOI：
10.3892/or.2015.4540
复制
发表时间：
2016-03-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Xiujun
中科院分区：
文献类型：
--
作者：
Hu, Fen;Zhang, Yunfeng;Zhang, Xiujun
骨形态发生蛋白-6(BMP-6)是一种多功能分子，具有不同的胚胎发生和器官发生能力。本研究结果表明，BMP-6在乳腺癌组织中的阴性表达率为30.56%，而在正常组织中为9.58%。这提示BMP-6在乳腺癌组织中不表达，可能抑制乳腺癌的转移。此外，还建立了BMP-6在MDA-MB-231细胞中的稳定过表达，以分析其转移能力。Boyden小室实验表明，BMP-6抑制了MDA-MB-231细胞的迁移和侵袭。实时定量聚合酶链式反应分析显示，BMP-6显著下调了MDA-MB-231细胞中基质金属蛋白酶-1(MMP1)的表达。重要的是，荧光素酶和芯片检测结果表明，BMP-6通过AP-1反应元件抑制了MMP-1启动子的活性。在BMP-6处理的MDA-MB-231细胞中，AP-1组分c-jun/c-Fos对内源性基质金属蛋白酶-1启动子的募集显著减少。我们还证明了BMP-6抑制了MDA-MB-231细胞的侵袭，这种作用被过表达的基质金属蛋白酶-1显著减弱。相反，用RNA干扰或基质金属蛋白酶-1抑制剂抑制基质金属蛋白酶-1则表现出相反的作用。这些观察表明，BMP-6通过调节肿瘤微环境中MMPs的分泌，在抑制乳腺癌转移方面发挥了新的作用。
Bone morphogenetic protein-6 (BMP-6) is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis. In the present study, our results showed that the rate of BMP-6-negative expression was 30.56% in breast cancer tissues, but was 9.58% in normal tissues by immunohistochemical staining. This implied that BMP-6 expression is absent in breast cancer tissues and may suppress breast cancer metastasis. In addition, stable overexpression of BMP-6 in MDA-MB-231 cells was established to analyze the metastatic ability. The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MDA-MB-231 cells. Moreover, real-time PCR analysis showed that BMP-6 markedly downregulated matrix metalloproteinase-1 (MMP-1) expression at both the mRNA and protein levels in the MDA-MB-231 cells. Importantly, the results of luciferase and CHIP assays revealed that BMP-6 inhibited MMP-1 promoter activity through the AP-1 response element. In MDA-MB-231 cells treated with BMP-6, a significant decrease in the recruitment of AP-1 components, c-Jun/c-Fos, to the endogenous MMP-1 promoter was noted. We also demonstrated that BMP-6 inhibited the invasion of MDA-MB-231 cells, and this effect was significantly attenuated by overexpression of MMP-1. In contrast, MMP-1 knockdown by RNA interference or MMP-1 inhibitor exhibited an opposite effect. These observations suggest a novel role of BMP-6 in the inhibition of breast cancer metastasis by regulating secretion of MMPs in the tumor microenvironment.