BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway
BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway
复制标题
DOI：
10.1016/j.yexcr.2009.10.010
复制
发表时间：
2010-01-01
影响因子：
3.7
通讯作者：
Yoo, Young A.
中科院分区：
文献类型：
--
作者：
Kang, Myoung Hee;Kim, Jun Suk;Yoo, Young A.
骨形态发生蛋白及其受体的上调是肿瘤进展的重要标志，因为它通过自分泌和旁分泌机制促进肿瘤的发展、侵袭和转移。一般来说，移动性和侵袭性的增加与上皮-间充质转化(EMT)呈正相关。本研究旨在探讨诱导胃癌细胞侵袭的BMP-2信号是否通过磷脂酰肌醇3-激酶(PI3K)/Akt途径。在此，我们发现胃癌细胞株表达BMP-2信号的所有成分，尽管表达程度不同。此外，BMP-2浓度的增加显著增强了胃癌细胞的运动能力和侵袭力，而在Noggin(BMP-2抑制剂)或BMP-2阻断抗体处理的细胞中没有观察到增加。BMP-2在胃癌细胞中的刺激诱导了以蜗牛诱导、E-钙粘蛋白非定位化和下调、间质和侵袭性标志物上调为特征的完整EMT。此外，用Noggin或BMP-2阻断抗体阻断BMP-2信号也能恢复EMT标志物的这些变化。此外，BMP-2可促进ALA的磷酸化，但不能促进Noggin或BMP-2阻断抗体的作用。用PI-3激酶/Akt激酶抑制剂(Kinase-Dead Ala[dN-Akt]、Akt siRNA或LY294002)预处理胃癌细胞可显著抑制BMP-2诱导的EMT和侵袭力。总之，我们的研究表明，BMP-2通过激活PI-3激酶/Akt来促进胃癌细胞的运动和侵袭，靶向该信号通路可能为预防BMP-2介导的转移提供治疗机会。(C)2009 Elsevier Inc.保留所有权利。
Up-regulation of bone morphogenetic proteins (BMPs) and their receptors by tumor is all important hallmark in cancer progression, as it contributes through autocrine and paracrine mechanisms to tumor development, invasion, and metastasis. Generally, increased motility and invasion are positively correlated with the epithelial-mesenchymal transition (EMT). The purpose of the present study was to determine whether BMP-2 signaling to induce gastric cancer cells to undergo EMT-mediated invasion might pass through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Herein we showed that gastric cancer cell lines express all the components of BMP-2 signaling, albeit to different extents. Moreover, an increased concentration of BMP-2 strongly enhanced motility and invasiveness in gastric cancer cells, whereas no increase was observed in cells treated with either Noggin (a BMP-2 inhibitor) or BMP-2 blocking antibodies. The stimulation of BMP-2 in gastric cancer cells induces a full EMT characterized by Snail induction, E-cadherin delocalization and down-regulation, and up-regulation of mesenchymal and invasiveness markers. Furthermore, blockade of BMP-2 signaling by Noggin or BMP-2 blocking antibodies also restored these changes in EMT markers. In addition, phosphorylation of Ala was also enhanced by treatment with BMP-2, but not Noggin or BMP-2 blocking antibodies. Pretreatment of gastric cancer cells with PI-3 kinase/Akt kinase inhibitor (kinase-dead Ala [DN-Akt], Akt siRNA, or LY294002) significantly inhibited BMP-2-induced EMT and invasiveness. Overall, our studies suggest that BMP-2 promotes motility and invasion of gastric cancer cells by activating PI-3 kinase/Akt and that targeting of this signaling pathway may provide therapeutic opportunities in preventing metastasis mediated by BMP-2. (C) 2009 Elsevier Inc. All rights reserved.