Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line
Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line
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DOI：
10.1002/jcp.21148
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发表时间：
2007-12-01
影响因子：
5.6
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Hamada, Shin;Satoh, Kennichi;Shimosegawa, Tooru
在我们的研究中，我们发现骨形态发生蛋白4（BMP 4）作为上皮间质转化（EMT）的诱导剂对人胰腺癌细胞系Panc-I细胞具有新的作用。BMP-4处理的Panc-I细胞显示松散的细胞接触和分散的成纤维细胞样外观沿着E-cadherin小丑调节、波形蛋白上调和增强的细胞迁移，这是EMT的特征。BMP 4处理还诱导同源框基因MSX 2的表达，我们以前在胰腺癌细胞中发现该基因与EMT相关。BMP 4处理激活了这些细胞中的Smad信号通路、细胞外信号相关激酶（ERK）和p38丝裂原活化激酶（MAPK）通路。BMP 4通过ERK和p38 MAPK通路协同Smad信号通路显著诱导MSX 2。当用BMP 4处理基于siRNA的MSX 2下调的胰腺癌细胞时，E-钙粘蛋白的抑制、波形蛋白的诱导和增强的细胞迁移消失。这些发现表明BMP 4可能通过促进EMT参与胰腺癌的发展，而MSX 2在此过程中是不可或缺的。
In our study, we found that bone morphogeretic protein 4 (BMP4) has a novel effect as an inducer of epithelial-mesenchymal transition (EMT) on Panc-I cells, a human pancreatic carcinoma cell line. BMP4-treated Panc-I cells showed loose cell contacts and a scattered, fibroblast-like appearance along with E-cadherin clownregulation, Vimentin upregulation and enhanced cell migration, which are characteristic of EMT. BMP4 treatment also induced homeobox gene MSX2 expression, which we previously showed to be associated with EMT in pancreatic carcinoma cells. BMP4 treatment activated the Smad signaling pathway, and extracellular signal-related kinase (ERK) and p38 mitogen-activated kinase (MAPK) pathways in these cells. MSX2 was markedly induced by BMP4 through the ERK and p38 MAPK pathways in collaboration with the Smad signaling pathway. The repression of E-cadherin, induction of Vimentin and enhanced cell migration disappeared when siRNA-based MSX2 downregulated pancreatic cancer cells were treated with BMP4. These findings indicate that BMP4 may be involved in pancreatic carcinoma development through the promotion of EMT and that MSX2 is indispensable to this process.