title: Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma.
abstract: Neuroblastoma is the most common extracranial solid tumor in childhood and is associated with serious morbidity and mortality. The effective treatment of neuroblastoma remains one of the major challenges in pediatric oncology. The Wnt signaling pathway has been shown to play a significant role in the pathogenesis of adult and pediatric tumors. WIF-1 has been identified as an important Wnt antagonist which inhibits Wnt/β-catenin signaling by directly binding to Wnt proteins. However, the expression and function of WIF-1 in neuroblastoma remains unknown. The present study showed that WIF-1 was downregulated with high level promoter methylation in neuroblastoma cells, and was significantly upregulated after exposure to demethylating agent. This finding suggests that downregulation of WIF-1 was associated with its promoter methylation in neuroblastoma. To further study the potential function of WIF-1 in neuroblastoma, we constructed a plasmid that over-expressed WIF-1 and transfected the plasmid into one neuroblastoma cell line SK-N-SH. We found that restoration of WIF-1 inhibited the growth and proliferation of neuroblastoma cells in vitro. Moreover, Wnt/β-catenin signaling activity and target genes expression were reduced by WIF-1 restoration. These results provide support that WIF-1 is downregulated and functions as a tumor suppressor by antagonizing Wnt/β-catenin signaling in neuroblastoma, suggesting a potential role as a therapeutic target in neuroblastoma.
authors.affiliation: Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Keling
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Pingqian
authors.initials: P
authors.lastname: Bao
authors.affiliation: Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
authors.forename: Jiaxiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Zongguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Division of Oncology, Department of Clinical and Experimental Medicine Faculty of Health Sciences, Country Council of Östergötland, University of Linköping, Linköping S-581 85, Sweden.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: liyuanletters@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D004791:Enzyme Inhibitors; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C485569:WIF1 protein, human; D051176:beta Catenin; D019938:Cyclin D1; D015254:DNA Modification Methylases
keywords: Methylation; Neuroblastoma; Wnt inhibitory factor-1 (WIF-1); Wnt/β-catenin signaling