©　2018　The　Author(s).　Published　by　S.　Karger　AG,　Basel.　Background/Aims:　Choriocarcinoma　(CC)　is　a　highly　aggressive　gestational　trophoblastic　neoplasia;　however,　the　underlying　molecular　mechanisms　of　its　invasiveness　and　metastasis　remain　poorly　understood.　Human　secreted　frizzled-related　protein　2　(SFRP2)　could　function　as　a　tumor　promoter　or　suppressor　in　different　tumors,　yet　the　role　it　plays　in　CC＇s　invasion　and　metastasis　is　thoroughly　unclear.　The　current　study　was　aimed　to　explore　the　function　and　underlying　mechanism　of　SFRP2　in　CC.　Methods:　The　expression　of　SFRP2　in　CC　tissues　was　examined　via　immunohistochemistry.　The　methylation　level　and　expression　of　SFRP2　in　CC　cell　lines,　JEG-3　and　JAR　were　examined　via　bisulfite　sequencing　PCR　(BSP),　western　blotting　and　quantitative　RT-PCR.　The　biological　role　of　increasing　expressed　SFRP2　through　its　promoter　demethylation　with　5-Aza-2＇-deoxycytidine　(5-Aza)　was　examined　by　a　series　of　in　vitro　functional　studies.　Furthermore,　lentivirus　transfection　technology　was　adopted　to　investigate　the　biological　roles　of　SFRP2　knockdown　in　JEG-3　and　JAR　cells　in　vitro　and　in　vivo.　Moreover,　its　downstream　signaling　pathway　was　investigated.　Results:　SFRP2　was　downregulated　in　CC　tissues,　and　its　expression　was　inversely　related　to　its　promoter　hypermethylation　frequency　in　JEG-3　and　JAR　cells.　Increased　SFRP2　through　its　promoter　demethylation　inhibited　cell　migration,　invasion　and　colony　formation　in　JEG-3　and　JAR　cells,　whereas　decreased　SFRP2　reversed　the　epithelial-mesenchymal　transition　(EMT)　process　and　stemness　in　JEG-3　and　JAR　cells　both　in　vitro　and　vivo.　Mechanistically,　SFRP2　regulated　the　EMT　and　stemness　of　CC　cell　lines　via　canonical　Wnt/β-catenin　signaling,　validated　by　the　usage　of　a　Wnt　activator　and　inhibitor.　Conclusion:　The　current　study　indicates　that　downregulated　SFRP2　has　potent　tumor-promotive　effects　in　CC　through　the　modulation　of　cancer　stemness　and　the　EMT　phenotype　via　activation　of　Wnt/β-catenin　signaling　in　vitro　and　in　vivo.