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.

中文翻译：

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SFRP5的表观遗传沉默通过表达抑制和Wnt信号通路激活促进软骨肉瘤的转移和侵袭

背景/目标

Wnt /β-catenin信号传导的异常激活可能与分泌的卷曲相关蛋白家族（SFRPs）的成员拮抗，与肿瘤的发生和发展有关。但是，关于软骨肉瘤中Wnt /β-catenin途径的SFRP5功能尚不清楚。这项研究旨在研究SFRP5启动子甲基化在软骨肉瘤转移和通过激活典型Wnt信号通路入侵中的潜在作用。

方法与结果

结果表明，在软骨肉瘤细胞系中，在mRNA和蛋白水平上，SFRP5启动子被甲基化，并且SFRP5表达显着降低。Wnt /β-catenin的经典信号通过去磷酸化和易位进入核内，被β-catenin稳定地激活。DNA甲基转移酶抑制剂5-Aza-2'-脱氧胞苷（5-Aza-dC）通过抑制SFRP5的甲基化并促进其表达来显着抑制软骨肉瘤细胞的增殖。5-Aza-dC处理和SFRP5过表达均可通过失活Wnt /β-catenin信号通路并促进软骨肉瘤细胞间充质-上皮转化（MET）来显着抑制软骨肉瘤细胞的转移和侵袭。

结论

我们所有的结果都表明，启动子甲基化对SFRP5的表观遗传沉默在软骨肉瘤的发展和通过SFRP5 / Wnt /β-catenin信号转移的转移中起着关键作用。其水平的调节可作为软骨肉瘤新治疗策略的潜在靶标和诊断工具。