期刊
CELLULAR SIGNALLING
卷 24, 期 12, 页码 2273-2282出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2012.08.004
关键词
Bladder cancer; Bone metastasis; Mesenchymal-to-epithelial transition; ZEB1; PI3K/Akt; GSK3 beta/beta-catenin
类别
资金
- 13115 Scientific and Technological Innovation Project of Shaanxi Province, China [2008ZDKJ-63]
- National Natural Science Foundation of China [NSFC 30701009, NSFC 81072105]
Muscle-invasive bladder cancer is associated with a high frequency of metastasis, and bone is the most common metastatic site outside the pelvis. To clarify its organ-specific characteristics, we generated a successive bone metastatic T24-B bladder cancer subline following tail vein injection of metastatic T24-L cells. Compared with parental T24-L cells, epithelial-like T24-B cells displayed increased adhesion but decreased migration or invasion abilities as well as up-regulation of cytokeratins and down-regulation of vimentin, N-cadherin and MMP2. Mechanically, phosphatidylinositol 3-kinase (PI3K)/Akt targets glycogen synthase kinase-3 beta (GSK3 beta)/beta-catenin to control ZEB1 gene transcription, and then subsequently regulates the expression of cytokeratins, vimentin and MMP2. Importantly, ZEB1 is essential for bladder cancer invasion in vitro and distant metastasis in vivo, and ZEB1 overexpression was highly correlated with the expression of those downstream markers in clinical tumor samples. Overall, this study reveals a novel mechanism facilitating metastatic bladder cancer cell re-colonization into bone, and confirms the significance of mesenchymal-to-epithelial transition (MET) in formation of bone metastasis. (c) 2012 Elsevier Inc. All rights reserved.
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