Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer.
Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer.
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将FGFR4鉴定为高级高级浆液卵巢癌的潜在治疗靶标。
DOI：
10.1158/1078-0432.ccr-12-2736
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发表时间：
2013-02-15
期刊：
影响因子：
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通讯作者：
Mok SC
中科院分区：
文献类型：
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作者：
Zaid TM;Yeung TL;Thompson MS;Leung CS;Harding T;Co NN;Schmandt RS;Kwan SY;Rodriguez-Aguay C;Lopez-Berestein G;Sood AK;Wong KK;Birrer MJ;Mok SC
目的：评价成纤维细胞生长因子受体4(FGFR4)蛋白在晚期高级别浆液性卵巢癌中的表达对预后的预测价值，探讨FGFR4在卵巢癌进展中的作用，评价FGFR4靶向治疗浆液性卵巢癌的可行性。对183例卵巢肿瘤标本进行FGFR4免疫组织化学定位。通过Kaplan-Meier和Cox回归分析，收集到的FGFR4表达数据与总生存率相关。通过将FGFR4特异性小干扰RNA(SiRNAs)导入卵巢癌细胞，观察FGFR4沉默对卵巢癌细胞生长、存活、侵袭、凋亡及FGF1介导的信号通路激活的影响。采用小鼠原位移植模型，观察注射FGFR4特异性siRNAs和FGFR4TRAP蛋白纳米脂质体对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沉默可显著降低卵巢癌细胞的增殖、存活和侵袭力，增加细胞凋亡率。此外，FGFR4的下调显著取消了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。体内靶向FGFR4的FGFR4特异性siRNAs和FGFR4 TRAP蛋白显著降低卵巢肿瘤的生长。FGFR4是晚期高级别浆液性卵巢癌的预后指标。抑制FGFR4和抑制配体-受体结合显著降低卵巢肿瘤的生长，提示靶向FGFR4蛋白高表达的卵巢癌细胞是一种新的治疗方法，将提高卵巢癌的存活率。
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 performed 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 small interfering RNAs (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 (NFκB), 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.