6423

SFRP2

Secreted frizzled-related proteins (SFRPs), containing five family members (SFRPs 1-5) are putative extracellular Wnt inhibitors. Given their abilities to inhibit Wnt signalling, as well as the loss of SFRP1 in many cancers, this family is generally considered to be tumour suppressive. In this study we analyzed gene expression, promoter methylation and survival data from over 8000 tumour and normal samples from 29 cancers in order to map the context-specific associations of SFRPs 1-5 with patient survival, gene silencing and gene expression signatures. We show that only SFRP1 associates consistently with tumour suppressive functions, and that SFRP2 and SFRP4 typically associate with a poor prognosis concomitant with the expression of genes associated with epithelial-to-mesenchymal transition. Moreover, our results indicate that while SFRP1 is lost in cancer cells via the process of DNA methylation, SFRP2 and 4 are likely derived from the tumour stroma, and thus tend to increase in tumours as compared to normal tissues. This in-depth analysis highlights the need to study each SFRP as a separate entity and suggests that SFRP2 and SFRP4 should be approached as complex matricellular proteins with functions that extend far beyond their putative Wnt antagonistic ability.

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 TET1 in EOC cell lines and primary samples was examined by western blot and immunohistochemistry. The biological role of ectopic TET1 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 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: TET1 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 TET1 inhibited colony formation, cell migration and invasion in SKOV3 and OVCAR3 cells. Furthermore, TET1 overexpression reversed the epithelial-mesenchymal transition (EMT) process of SKOV3 cells. Mechanistically, TET1 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 TET1 has potent tumor-suppressive effects in EOC by activating Wnt/beta-catenin signaling inhibitors DKK1 and SFRP2.CI - Copyright (c) 2017. Published by Elsevier Inc.

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/beta-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/beta-catenin signaling in vitro and in vivo.CI - (c) 2018 The Author(s). Published by S. Karger AG, Basel.