Insulin-like growth factor-l-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells
Insulin-like growth factor-l-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells
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DOI：
10.1158/0008-5472.can-07-2559
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发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
O'Regan, Ruth M.
中科院分区：
文献类型：
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作者：
Graham, Tisheeka R.;Zhau, Haiyen E.;O'Regan, Ruth M.
上皮-间质转化（EMT）是许多上皮肿瘤（包括前列腺癌）迁移和侵袭的关键。尽管已知在多种癌症中ZEB 1过表达主要通过下调E-钙粘蛋白促进EMT，但负责ZEB 1活化的可溶性配体尚未被鉴定。在本研究中，我们研究了胰岛素样生长因子-I（IGF-I）在前列腺肿瘤细胞迁移相关的EMT过程中对ZEB 1的调节作用。我们发现ZEB 1在高度侵袭性的前列腺癌细胞中表达，并且其表达与人前列腺肿瘤的Gleason分级直接相关（P < 0.001）。IGF-I上调ZEB 1在前列腺癌细胞中的表达，表现为上皮表型。在显示间充质表型的前列腺癌细胞中，ZEB 1抑制逆转了E-钙粘蛋白的抑制，并下调了间充质标志物N-钙粘蛋白和纤连蛋白的表达。此外，与对照组相比，ZEB 1阻断降低了ARCaP（M）的迁移和侵袭潜力。这些结果确定ZEB 1作为前列腺癌中EMT的关键转录调节因子，并表明前列腺癌细胞中ZEB 1的异常表达部分地响应于IGF-I刺激。
The epithelial-to-mesenchymal transition (EMT) is crucial for the migration and invasion of many epithelial tumors, including prostate cancer. Although it is known that ZEB1 overexpression promotes EMT primarily through down-regulation of E-cadherin in a variety of cancers, the soluble ligands responsible for the activation of ZEB1 have yet to be identified. In the present study, we investigated the role of insulin-like growth factor-I (IGF-I) in the regulation of ZEB1 during EMT associated with prostate tumor cell migration. We found that ZEB1 is expressed in highly aggressive prostate cancer cells and that its expression correlates directly with Gleason grade in human prostate tumors (P < 0.001). IGF-I up-regulates ZEB1 expression in prostate cancer cells exhibiting an epithelial phenotype. In prostate cancer cells displaying a mesenchymal phenotype, ZEB1 inhibition reverses the suppression of E-cadherin protein and down-regulates the expression of the mesenchymal markers N-cadherin and fibronectin. Furthermore, ZEB1 blockade decreases migratory and invasive potential in ARCaP(M) compared with the control. These results identify ZEB1 as a key transcriptional regulator of EMT in prostate cancer and suggest that the aberrant expression of ZEB1 in prostate cancer cells occurs in part in response to IGF-I stimulation.