Clusterin Mediates TGF-β-Induced Epithelial-Mesenchymal Transition and Metastasis via Twist1 in Prostate Cancer Cells
Clusterin Mediates TGF-β-Induced Epithelial-Mesenchymal Transition and Metastasis via Twist1 in Prostate Cancer Cells
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DOI：
10.1158/0008-5472.can-12-0254
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发表时间：
2012-10-15
期刊：
影响因子：
11.2
通讯作者：
Gleave, Martin E.
中科院分区：
文献类型：
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作者：
Shiota, Masaki;Zardan, Anousheh;Gleave, Martin E.
TGF-β促进上皮-间充质转化（EMT）并诱导丛生蛋白（CLU）表达，将这些基因与癌症转移联系起来。CLU是一种多效性分子伴侣，赋予癌细胞存活和增殖优势。然而，TGF-β调节CLU表达和CLU影响转移的分子机制仍然未知。在这项研究中，我们报告说，转录因子Twist 1介导TGF-β诱导的CLU表达。Twist 1通过与CLU基因启动子远端的E-box结合，调控CLU基因的基础转录和TGF-β诱导的转录。此外，CLU减少减少了TGF-β诱导的间充质标记物，N-钙粘蛋白和纤连蛋白，从而抑制了TGF-β诱导的迁移和侵袭特性。CLU的靶向抑制也抑制了体内模型中的转移。总之，我们的研究结果表明，CLU是TGF-β诱导的EMT的重要介质，并表明CLU抑制可能是一个有前途的治疗选择，抑制前列腺癌转移进展。Cancer Res; 72（20）; 5261-72. (C)2012年AACR。
TGF-beta promotes epithelial-mesenchymal transition (EMT) and induces clusterin (CLU) expression, linking these genes to cancer metastasis. CLU is a pleiotropic molecular chaperone that confers survival and proliferative advantage to cancer cells. However, the molecular mechanisms by which TGF-beta regulates CLU expression and CLU affects metastasis remain unknown. In this study, we report that the transcription factor Twist1 mediates TGF-beta-induced CLU expression. By binding to E-boxes in the distal promoter region of CLU gene, Twist1 regulated basal and TGF-beta-induced CLU transcription. In addition, CLU reduction reduced TGF-beta induction of the mesenchymal markers, N-cadherin and fibronectin, thereby inhibiting the migratory and invasive properties induced by TGF-beta. Targeted inhibition of CLU also suppressed metastasis in an in vivo model. Taken together, our findings indicate that CLU is an important mediator of TGF-beta-induced EMT, and suggest that CLU suppression may represent a promising therapeutic option for suppressing prostate cancer metastatic progression. Cancer Res; 72(20); 5261-72. (C) 2012 AACR.