Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC.
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.
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Xian-Yue
XY
Ren
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Guan-Qun
GQ
Zhou
Department of Radiation Oncology, Guilin Medical University Affiliated Hospital, Guilin, PR China.
Wei
W
Jiang
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Ying
Y
Sun
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Ya-Fei
YF
Xu
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Ying-Qin
YQ
Li
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Xin-Ran
XR
Tang
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Xin
X
Wen
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Qing-Mei
QM
He
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
Xiao-Jing
XJ
Yang
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China. majun2@mail.sysu.edu.cn liun1@sysucc.org.cn.
Na
N
Liu
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology, South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China. majun2@mail.sysu.edu.cn liun1@sysucc.org.cn.
Jun
J
Ma
D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000094742:Secreted Frizzled-Related Proteins
D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins