Abstract
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/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; 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. β-Catenin, c-Myc, and cyclin D1 were downregulated after SFRP1 restoration, which suggested that SFRP1 suppressed growth and metastasis by inhibiting the Wnt/β-catenin signaling pathway in NPC. SFRP1 provides further insight into NPC progression and may provide novel therapeutic targets for NPC treatment.
Highlights
Nasopharyngeal carcinoma (NPC) is one of the leading malignancies of the head and neck; prevalence is low (0.5 cases per 100,000 individuals) in Europe and the United States, but the incidence rate is high (20–50 cases per 100,000 people) in southern China [1]
Low Secreted frizzled-related protein 1 (SFRP1) expression was associated with worse survival in NPC
We showed that 48.8% of patients with NPC had low SFRP1 expression and that low SFRP1 expression was significantly associated with poor survival
Summary
Nasopharyngeal carcinoma (NPC) is one of the leading malignancies of the head and neck; prevalence is low (0.5 cases per 100,000 individuals) in Europe and the United States, but the incidence rate is high (20–50 cases per 100,000 people) in southern China [1]. Improvements in intensity-modulated radiotherapy and chemotherapy have improved local control. The outcome remains poor for approximately 30% of patients with NPC. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).
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