Epigenetic silencing of SFRP5 promotes the metastasis and invasion of chondrosarcoma by expression inhibition and Wnt signaling pathway activation.

BACKGROUD/AIMS:Abnormal activation of the Wnt/β-catenin signaling, which may be antagonized by the members of secreted frizzled-related proteins family (SFRPs), is implicated in tumor occurrence and development. However, the function of SFRP5 relating to Wnt/β-catenin pathway in chondrosarcoma is not clear yet. This study was undertaken to investigate the potential role of SFRP5 promoter methylation in chondrosarcoma metastasis and invasion through activating canonical Wnt signaling pathway. METHODS AND RESULTS:The results demonstrated that SFRP5 promoter was hypermethylated and SFRP5 expression was significantly reduced in chondrosarcoma cell lines at the mRNA and protein levels. The canonical Wnt/β-catenin signaling was observably activated with β-catenin stabilization by dephosphorylation and translocation into the nuclear. 5-Aza-2'-deoxycytidine (5-Aza-dC), the DNA methyltransferase inhibitor, significantly inhibited the proliferation of chondrosarcoma cells by cell cycle arrest through repressing the methylation of SFRP5 and promoting its expression. Both 5-Aza-dC treatment and SFRP5 overexpression could significantly inhibited the metastasis and invasion of chondrosarcoma cells by inactivating Wnt/β-catenin signaling pathway and promoting chondrosarcoma cells mesenchymal-epithelial transition (MET). 5-Aza-dC also inhibited the xenograft growth and lung metastasis of chondrosarcoma cells in vivo via suppressing SFRP5 promotor methylation, inactivating Wnt/β-catenin pathway and inducing epithelial markers expression. CONCLUSION:All of our results revealed the epigenetic silencing of SFRP5 by promoter methylation plays pivotal roles in chondrosarcoma development and metastasis through SFRP5/Wnt/β-catenin signaling axis. Modulation of their levels may serve as potential targets and diagnostic tools for novel therapeutic strategies of chondrosarcoma.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}