Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells

Yi Guo, Xiaolin Zi, Zach Koontz, Alison Kim, Jun Xie, Richard Gorlick, Randall F. Holcombe, Bang H. Hoang

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

We previously reported the Wnt receptor low-density lipoprotein receptor-related protein 5 (LRP5) was frequently expressed in osteosarcoma (OS) tissue and correlated with metastasis and a lower disease-free survival. Subsequent in vitro analysis revealed that dominant-negative, soluble LRP5 (sLRP5) can reduce in vitro cellular invasion. In the current study, we examined the molecular mechanisms of blocking canonical Wnt signaling by sLRP5 in Saos-2 osteosarcoma cells. Transfection of sLRP5 caused a marked up-regulation of E-cadherin in this cell line. This increase in E-cadherin, seen primarily at the cell - cell contact borders, was associated with down-regulation of Slug and Twist, transcriptional repressors which mediate cancer invasion and metastasis. In contrast, N-cadherin, a mesenchymal marker, was reduced by sLRP5. In addition, blocking Wnt signaling by sLRP5 modulated other epithelial and mesenchymal markers (keratin 8 and 18, fibronectin), suggesting a reversal of epithelial-mesenchymal transition (EMT) seen during cancer progression. SLRP5 also reduced the expression of matrix metalloproteinase (MMP) 2 and 14, consistent with a decrease in invasive capacity. SLRP5 transfection decreased both Met expression and hepatocyte growth factor (HGF)-induced cell motility. Taken together, these results support a role for Wnt/LRP5 signaling in invasiveness of a subset of OS cells.

Original languageEnglish (US)
Pages (from-to)964-971
Number of pages8
JournalJournal of Orthopaedic Research
Volume25
Issue number7
DOIs
StatePublished - Jul 2007

Keywords

  • Cadherin
  • Low-density lipoprotein receptor-related protein 5
  • Metastasis
  • Osteosarcoma
  • Wnt signaling

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

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