TETI inhibits EMT of ovarian cancer cells through activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2

Objective. Epithelial ovarian cancer (EOC) is the deadliest type of ovarian cancer, but the mechanisms contributing to its tumorigenesis are not well understood. Herein, we will elucidate the role of Ten-eleven translocation 1 (TET1) in EOC development Methods. The expression of TETI in EOC cell lines and primary samples was examined by western blot and immunohistochemistry. The biological role of ectopic TETI overexpression was revealed by a series of in vitro functional studies. Its downstream signaling pathway was predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of microarray data. The methylation level and expression of Wnt/beta-catenin signaling inhibitors Dikkopf 1 (DKK1) and secreted Fzd receptor protein 2 (SFRP2) were examined by Chromatin immunoprecipitation (ChIP) assay, Epimark (TM) 5hmC and 5mC level analysis and quantitative RT-PCR Small interference RNA (siRNA) technology was used to investigate the biological roles of DKK1 and SFRP2. Results. TETI expression was inversely correlated with clinical stage in patients with EOC by tissue microarray (TMA).TET1 expression was undetected in 6 types of EOC cell lines. Ectopic expression of TETI inhibited colony formation, cell migration and invasion in SKOV3 and OVCAR3 cells. Furthermore, TM overexpression reversed the epithelial-mesenchymal transition (EMT) process of SKOV3 cells. Mechanistically, TETI potently inhibited canonical Wnt/beta-catenin signaling by demethylating and upregulating two upstream antagonists of this pathway, SFRP2 and DKK1, which was associated with inhibition of EMT and cancer cell metastasis. Conclusion. This study uncovers that TETI has potent tumor-suppressive effects in EOC by activating Wnt/beta-catenin signaling inhibitors Dial and SFRP2. (C) 2017 Published by Elsevier Inc.