Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Clin Cancer Res. 2013 Feb 15;19(4):809-20. doi: 10.1158/1078-0432.CCR-12-2736. Epub 2013 Jan 23.
To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment.
Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan-Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo.
Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo.
FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it.
评估成纤维细胞生长因子受体 4（FGFR4）蛋白表达在晚期高级别浆液性卵巢癌患者中的预后价值，阐明 FGFR4 在卵巢癌进展中的功能作用，并评估针对 FGFR4 在浆液性卵巢癌治疗中的可行性。
对 183 个卵巢肿瘤样本进行 FGFR4 的免疫组化定位。收集的 FGFR4 表达数据通过 Kaplan-Meier 和 Cox 回归分析与总生存期相关。通过转染 FGFR4 特异性 siRNA 评估 FGFR4 沉默对卵巢癌细胞生长、存活、侵袭性、凋亡和 FGF1 介导的信号通路激活的影响。采用原位小鼠模型评估 FGFR4 特异性 siRNA 和包裹在纳米脂质体中的 FGFR4 陷阱蛋白注射对体内卵巢肿瘤生长的影响。
FGFR4 蛋白的过度表达与总生存期的缩短显著相关。FGFR4 沉默显著降低了卵巢癌细胞的增殖、存活和侵袭性，增加了凋亡。此外，下调 FGFR4 显著阻断了由 FGF1 激活的丝裂原活化蛋白激酶（MAPK）、核因子-κB（NF-κB）和 WNT 信号通路。用 FGFR4 特异性 siRNA 和 FGFR4 陷阱蛋白靶向 FGFR4 显著降低了体内卵巢肿瘤的生长。
FGFR4 是晚期高级别浆液性卵巢癌的预后标志物。沉默 FGFR4 和抑制配体-受体结合显著降低了体外和体内卵巢肿瘤的生长，表明针对高表达 FGFR4 蛋白的卵巢癌细胞是治疗该疾病的新方法，并将提高其生存率。
