Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC
复制标题
SFRP1 低表达与不良预后相关，并通过激活 NPC 中的 Wnt/β-Catenin 信号通路促进细胞侵袭
DOI：
10.1158/1940-6207.capr-14-0369
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发表时间：
2015-10-01
影响因子：
3.3
通讯作者：
Ma, Jun
中科院分区：
文献类型：
--
作者：
Ren, Xian-Yue;Zhou, Guan-Qun;Ma, Jun
远处转移仍然是鼻咽癌（NPC）治疗失败的主要方式。不幸的是，人们对鼻咽癌转移的分子事件仍知之甚少。分泌型卷曲相关蛋白 1 (SFRP1) 在肿瘤的发生和进展中发挥着重要作用。然而，人们对SFRP1在鼻咽癌中的功能和机制知之甚少。采用免疫组织化学法测定鼻咽癌患者中 SFRP1 的表达水平。使用 MTT、集落形成、伤口愈合、Transwell 测定和体内模型评估 SFRP1 功能。使用硫酸氢盐焦磷酸测序检测鼻咽癌细胞中 SFRP1 的甲基化水平；使用蛋白质印迹法研究Wnt/β-连环蛋白信号通路基因。与SFRP1高表达患者相比，SFRP1低表达患者的总生存期较差[HR，2.32； 95%置信区间（CI），1.36-3.94； P = 0.002]、无病生存率（HR，1.98；95% CI，1.23-3.18；P = 0.005）和无远处转移生存率（HR，2.07；95% CI，1.19-3.59；P = 0.009）。多变量Cox回归分析表明SFRP1是一个独立的预后因素。此外，SFRP1 在 NPC 细胞系中显着下调。 SFRP1 过表达可抑制 NPC 细胞的体外增殖、迁移和侵袭以及体内肺定植。去甲基化剂处理后，SFRP1表达恢复，并且鼻咽癌细胞中SFRP1启动子区域高甲基化。 SFRP1恢复后β-Catenin、c-Myc和cyclin D1下调，这表明SFRP1通过抑制NPC中的Wnt/β-catenin信号通路来抑制生长和转移。 SFRP1 提供了对 NPC 进展的进一步了解，并可能为 NPC 治疗提供新的治疗靶点。 (C) 2015 年 AACR。
Distant metastasis remains the predominant mode of treatment failure in nasopharyngeal carcinoma (NPC). Unfortunately, the molecular events underlying NPC metastasis remain poorly understood. Secreted frizzled-related protein 1 (SFRP1) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of SFRP1 in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. SFRP1 function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and in vivo models. The methylation level of SFRP1 in NPC cells was examined using bisulfate pyrosequencing; the Wnt/beta-catenin signaling pathway genes were studied using Western blotting. Compared with patients with high SFRP1 expression, patients with low SFRP1 expression had worse overall survival [HR, 2.32; 95% confidence interval (CI), 1.36-3.94; P = 0.002], disease-free survival (HR, 1.98; 95% CI, 1.23-3.18; P = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19-3.59; P = 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, SFRP1 was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion in vitro and lung colonization in vivo. SFRP1 expression was restored after treatment with a demethylation agent, and the SFRP1 promoter region was hypermethylated in NPC cells. beta-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/beta-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment. (C) 2015 AACR.