Data from Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

Abstract

<div>Abstract<p>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 (<i>SFRP1</i>) plays an important role in tumorigenesis and progression. However, little is known about the function and mechanism of <i>SFRP1</i> in NPC. Immunohistochemistry was used to determine SFRP1 expression levels in patients with NPC. <i>SFRP1</i> function was evaluated using MTT, colony formation, wound-healing, Transwell assays, and <i>in vivo</i> models. The methylation level of <i>SFRP1</i> in NPC cells was examined using bisulfate pyrosequencing; the Wnt/β-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; <i>P</i> = 0.002], disease-free survival (HR, 1.98; 95% CI, 1.23–3.18; <i>P</i> = 0.005), and distant metastasis-free survival (HR, 2.07; 95% CI, 1.19–3.59; <i>P</i> = 0.009). Multivariate Cox regression analysis indicated that SFRP1 was an independent prognostic factor. Furthermore, <i>SFRP1</i> was significantly downregulated in NPC cell lines. SFRP1 overexpression suppressed NPC cell proliferation, migration, and invasion <i>in vitro</i> and lung colonization <i>in vivo</i>. <i>SFRP1</i> expression was restored after treatment with a demethylation agent, and the <i>SFRP1</i> promoter region was hypermethylated in NPC cells. β-Catenin, c-Myc, and cyclin D1 were downregulated after <i>SFRP1</i> restoration, which suggested that <i>SFRP1</i> suppressed growth and metastasis by inhibiting the Wnt/β-catenin signaling pathway in NPC. <i>SFRP1</i> provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment. <i>Cancer Prev Res; 8(10); 968–77. ©2015 AACR</i>.</p></div>