WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer.
WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer.
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我们先前描述了WNT7A与卵巢癌进展之间的联系。其他研究小组已将FGF1确定为卵巢癌的相关风险因素。在这里，我们显示了这两个信号通路之间的联系，这可能被用来改善卵巢癌患者的治疗和预后。WNT7A和FGF1的高表达与卵巢癌和患者总体生存不良相关。染色质免疫沉淀分析表明，WNT7A/β-catenin信号通过FGF1-1C启动子区域的Tcf结合元件直接调控FGF1的表达。体外基因操作研究表明，FGF1足以驱动WNT7A的促肿瘤作用。体内异种移植研究证实，WNT7A或FGF1的稳定过表达导致肿瘤发生率显著增加，而WNT7A高表达细胞中FGF1的敲除导致肿瘤体积显著减小。在我们的模型中，氯硝柳胺最有效地取消了WNT7A/β-连环蛋白信号转导，抑制了β-连环蛋白的转录活性和细胞活力，并增加了细胞死亡。此外，氯硝柳胺在E-钙粘附素增加后减少了细胞迁移，而鼻塞水平降低了。氯硝柳胺对细胞功能的影响在WNT7A高表达细胞中更为明显。口服氯硝柳胺可抑制代表人类卵巢癌的小鼠腹膜内移植瘤的生长和进展。综上所述，这些结果表明，FGF1是WNT7A/β-连环蛋白信号的直接下游靶点，该途径有可能成为卵巢癌的治疗靶点。此外，氯硝柳胺是一种很有前途的该途径的抑制剂，可能具有临床意义。
We previously characterized the link between WNT7A and the progression of ovarian cancer. Other groups have identified FGF1 as a relevant risk factor in ovarian cancer. Here, we show a linkage between these two signaling pathways that may be exploited to improve treatment and prognosis of patients with ovarian cancer. High expression of WNT7A and FGF1 are correlated in ovarian carcinomas and poor overall patient survival. A chromatin immunoprecipitation assay demonstrated that WNT7A/β-catenin signaling directly regulates FGF1 expression via TCF binding elements in the FGF1-1C promoter locus. In vitro gene manipulation studies revealed that FGF1 is sufficient to drive the tumor promoting effects of WNT7A. In vivo xenograft studies confirmed that the stable overexpression of WNT7A or FGF1 induced a significant increase in tumor incidence, while FGF1 knockdown in WNT7A overexpressing cells caused a significant reduction in tumor size. Niclosamide most efficiently abrogated WNT7A/β-catenin signaling in our model, inhibited β-catenin transcriptional activity and cell viability, and increased cell death. Furthermore, niclosamide decreased cell migration following an increase in E-cadherin subsequent to decreased levels of SLUG. The effects of niclosamide on cell functions were more potent in WNT7A overexpressing cells. Oral niclosamide inhibited tumor growth and progression in an intraperitoneal xenograft mouse model representative of human ovarian cancer. Collectively, these results indicate that FGF1 is a direct downstream target of WNT7A/β-catenin signaling and this pathway has potential as a therapeutic target in ovarian cancer. Moreover, niclosamide is a promising inhibitor of this pathway and may have clinical relevance.
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