title: Enhanced Wnt signaling by methylation-mediated loss of SFRP2 promotes osteosarcoma cell invasion.
abstract: Wnt signaling is essential for the initiation and progression of osteosarcoma (OS) tumors and is suppressed by the secreted frizzled-related proteins (SFRPs). The methylation-induced protein degradation reduces the activity of SFRPs and subsequently increases the activity of Wnt signaling. However, whether the methylation of SFRP2, a member of SFRPs, may be involved in the pathogenesis of OS is not known. Here, we investigated the expression levels of SFRP2 in OS specimens. We found that SFRP2 mRNA was significantly decreased and methylation of SFRP2 gene was significantly increased in malignant OS tumors as compared to the paired adjacent non-tumor tissue. Moreover, SFRP2 expression was significantly decreased in the malignant OS cell lines, SAOS2, MG63, and U2OS, but not in the primary osteoblast cells. The demethylation of SFRP2 gene by 5'-aza-deoxycytidine (5-aza-dCyd) in OS cell lines restored SFRP2 expression, at both mRNA and protein levels, and suppressed cell invasion. Furthermore, the demethylation of SFRP2 gene appeared to inhibit nuclear retention of a key Wnt signaling factor, β-catenin, in OS cell lines. Together, these data suggest that SFRP2 may function as an OS invasion suppressor by interfering with Wnt signaling, and the methylation of SFRP2 gene may promote pathogenesis of OS.
authors.affiliation: Department of Hand Surgery, The First Affiliated Hospital of Liaoning Medical University, 2 Renmin Road, Guta District, Jinzhou, 121001, China. qiang_xiao14@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Hand Surgery, The First Affiliated Hospital of Liaoning Medical University, 2 Renmin Road, Guta District, Jinzhou, 121001, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Hand Surgery, The First Affiliated Hospital of Liaoning Medical University, 2 Renmin Road, Guta District, Jinzhou, 121001, China.
authors.forename: Xuepu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hand Surgery, The First Affiliated Hospital of Liaoning Medical University, 2 Renmin Road, Guta District, Jinzhou, 121001, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: An
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D059748:Proteolysis; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; D051176:beta Catenin; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins
keywords: 5-aza-dCyd; Cancer invasion; Methylation; Osteosarcoma (OS); Secreted frizzled-related proteins (SFRPs); Wnt signaling; β-catenin