Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Int J Cancer. 2010 Aug 1;127(3):555-67. doi: 10.1002/ijc.25083.
Oncogenic activation of the Wnt signaling pathway is common in cancers, but mutation of beta-catenin in ovarian cancer is rare. In addition to genetic events, epigenetic modification of secreted frizzled-related protein (SFRP) family has been shown to be important in regulating Wnt signaling. Although high degree of homology is observed in the same family, different SFRPs may have opposing effects on the same process. We reported recently that a Wnt antagonist, SFRP5, is downregulated frequently through promoter hypermethylation and that this hypermethylation is associated with overall survival in ovarian cancer. The aim of this study was to analyze the function of SFRP5 in ovarian cancer. Functional assays including measuring cell proliferation, invasion, colony formation and xenograft were performed using ovarian cancer cell lines with overexpression of SFRP5 or a short hairpin RNA silencing. The methylation status of SFRP5 in relation to cisplatin resistance in ovarian cancer patients was analyzed. Restoration of the expression of SFRP5 attenuated Wnt signaling in ovarian cancer cells and suppressed cancer cell growth, invasion of cells and tumorigenicity in mice. These effects were independent of the canonical pathway. The expression of SFRP5 inhibited epithelial-mesenchymal transition (EMT). The restoration of SFRP5 downregulated AKT2 and sensitized ovarian cancer cells to chemotherapy. These effects are consistent with the poor response to platinum-based chemotherapy in patients with methylation of SFRP5. Our data suggested that epigenetic silencing of SFRP5 leads to oncogenic activation of the Wnt pathway and contributes to ovarian cancer progression and chemoresistance through the TWIST-mediated EMT and AKT2 signaling.
致癌激活 Wnt 信号通路在癌症中很常见，但在卵巢癌中β-连环蛋白的突变很少见。除了遗传事件外，分泌卷曲相关蛋白（SFRP）家族的表观遗传修饰已被证明在调节 Wnt 信号中很重要。尽管同一家族中观察到高度同源性，但不同的 SFRP 可能对同一过程产生相反的影响。我们最近报道，Wnt 拮抗剂 SFRP5 通过启动子超甲基化频繁下调，并且这种超甲基化与卵巢癌的总生存率相关。本研究的目的是分析 SFRP5 在卵巢癌中的功能。通过过表达 SFRP5 或短发夹 RNA 沉默的卵巢癌细胞系进行了包括测量细胞增殖、侵袭、集落形成和异种移植在内的功能测定。分析了 SFRP5 的甲基化状态与卵巢癌患者顺铂耐药的关系。SFRP5 的表达恢复减弱了卵巢癌细胞中的 Wnt 信号，并抑制了癌细胞的生长、侵袭和小鼠中的肿瘤形成。这些作用独立于经典途径。SFRP5 的表达抑制了上皮-间充质转化（EMT）。SFRP5 的恢复下调了 AKT2 并使卵巢癌细胞对化疗敏感。这些作用与 SFRP5 甲基化患者对铂类化疗反应不佳一致。我们的数据表明，SFRP5 的表观遗传沉默导致 Wnt 通路的致癌激活，并通过 TWIST 介导的 EMT 和 AKT2 信号通路促进卵巢癌的进展和化疗耐药。
