The Wnt gatekeeper SFRP4 modulates EMT, cell migration and downstream Wnt signalling in serous ovarian cancer cells.
The Wnt gatekeeper SFRP4 modulates EMT, cell migration and downstream Wnt signalling in serous ovarian cancer cells.
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DOI：
10.1371/journal.pone.0054362
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ward RL
中科院分区：
文献类型：
--
作者：
Ford CE;Jary E;Ma SS;Nixdorf S;Heinzelmann-Schwarz VA;Ward RL
异常的 Wnt 信号传导与多种人类癌症有关，了解通路成员的调节作用可能会导致新疗法的开发。分泌型卷曲相关蛋白 4 (SFRP4) 是 Wnt 信号通路的细胞外调节剂，其表达在更具侵袭性的卵巢癌表型中逐渐丧失。在这里，我们表明，重组 SFRP4 (rSFRP4) 处理浆液性卵巢癌细胞系可抑制 β-catenin 依赖性 Wnt 信号传导（通过 TOP/FOP Wnt 报告基因测定检测），并减少 Wnt 靶基因 Axin2、CyclinD1 和 Myc 的转录。此外，rSFRP4治疗显着增加了卵巢癌细胞粘附胶原蛋白和纤连蛋白的能力，并降低了它们在受伤伤口上迁移的能力。我们得出的结论是，细胞行为的这些变化可能是通过间充质到上皮转化（MET）介导的，因为 rSFRP4 治疗还导致上皮标记物 E-钙粘蛋白的表达增加，以及波形蛋白和 Twist 的表达减少。综合起来，这些结果表明，Wnt 信号传导的单个上游看门人的调节可以通过上皮间质可塑性 (EMP) 介导，对下游 Wnt 信号传导和卵巢癌细胞行为产生影响。这提出了SFRP4可用于上皮性卵巢癌的诊断和治疗的可能性。
Aberrant Wnt signalling is implicated in numerous human cancers, and understanding the effects of modulation of pathway members may lead to the development of novel therapeutics. Expression of secreted frizzled related protein 4 (SFRP4), an extracellular modulator of the Wnt signalling pathway, is progressively lost in more aggressive ovarian cancer phenotypes. Here we show that recombinant SFRP4 (rSFRP4) treatment of a serous ovarian cancer cell line results in inhibition of β-catenin dependent Wnt signalling as measured by TOP/FOP Wnt reporter assay and decreased transcription of Wnt target genes, Axin2, CyclinD1 and Myc. In addition, rSFRP4 treatment significantly increased the ability of ovarian cancer cells to adhere to collagen and fibronectin, and decreased their ability to migrate across an inflicted wound. We conclude that these changes in cell behaviour may be mediated via mesenchymal to epithelial transition (MET), as rSFRP4 treatment also resulted in increased expression of the epithelial marker E-cadherin, and reduced expression of Vimentin and Twist. Combined, these results indicate that modulation of a single upstream gatekeeper of Wnt signalling can have effects on downstream Wnt signalling and ovarian cancer cell behaviour, as mediated through epithelial to mesenchymal plasticity (EMP). This raises the possibility that SFRP4 may be used both diagnostically and therapeutically in epithelial ovarian cancer.
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