Secreted Frizzled Related Protein 2 Modulates Epithelial–Mesenchymal Transition and Stemness via Wnt/β-Catenin Signaling in Choriocarcinoma

Abstract

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.

Role of Chrysophanol in Epithelial‐Mesenchymal Transition in Oral Cancer Cell Lines via a Wnt‐3‐Dependent Pathway

“…Our results showed that chrysophanol inhibited the nuclear localization of β -catenin in FaDu cells ( Figure 3 ), which is in agreement with previous studies [ 35 , 36 ]. Furthermore, we further showed that the phenotype of EMT was reversed by Bml 284, which was consistent with previous studies [ 37 , 38 ]. On the other hand, substantial evidence has shown that Wnt-3 is a key regulator of cell proliferation and metastasis in colorectal cancer, gastric cancer development, and malignant melanoma [ 39 – 41 ].…”

IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway

“…When the Wnt ligand binds to the frizzled/lowdensity lipoprotein receptor-related protein (LRP) receptor complex, the Wnt/β-catenin cascade is activated, leading to the accumulation of β-catenin. Conversely, when the Wnt ligands are absent, or the frizzled/LRP receptor complex is blocked by the antagonists, cytoplasmic β-catenin is subsequently recruited to the destruction complex (DC) for degradation [28]. SFRP2 has been viewed as an antagonist of the Wnt/β-catenin pathway due to its homology with the extracellular (See figure on previous page.)…”

miRNA and mRNA expression profiles in gastric cancer patients and the relationship with circRNA

“…Subsequent pathway analysis showed that hsa-miR-375 was involved in the glypican pathway, regulation of CDC42 activity, CDC42 signaling, developmental biology, Wnt signaling pathway, glypican 3 network, etc. ( Figure S1D), which are highly correlated with immune processes [26] and tumor formation mechanisms [27,28], as well as other diseases [29,30].…”