PI3K/Akt to GSK3β/β-catenin signaling cascade coordinates cell colonization for bladder cancer bone metastasis through regulating ZEB1 transcription

Kaijie Wu, Jinhai Fan, Linlin Zhang, Zhongyun Ning, Jin Zeng, Jiancheng Zhou, Lei Li, Yule Chen, Tingting Zhang, Xinyang Wang, Jer Tsong Hsieh, Dalin He

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

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-3β (GSK3β)/β-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.

Original languageEnglish (US)
Pages (from-to)2273-2282
Number of pages10
JournalCellular Signalling
Volume24
Issue number12
DOIs
StatePublished - Dec 1 2012

Keywords

  • Bladder cancer
  • Bone metastasis
  • GSK3β/β-catenin
  • Mesenchymal-to-epithelial transition
  • PI3K/Akt
  • ZEB1

ASJC Scopus subject areas

  • Cell Biology

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