Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells
✍ Scribed by Yi Guo; Xiaolin Zi; Zach Koontz; Alison Kim; Jun Xie; Richard Gorlick; Randall F. Holcombe; Bang H. Hoang
- Publisher
- Elsevier Science
- Year
- 2007
- Tongue
- English
- Weight
- 273 KB
- Volume
- 25
- Category
- Article
- ISSN
- 0736-0266
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✦ Synopsis
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 s__LRP5__ 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. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:964–971, 2007