Abstract
BackgroundFOXD3 is aberrantly regulated in several tumors, but its underlying mechanisms in ovarian cancer (OC) remains largely unknown. The present study aimed to explore the role and associated mechanisms of FOXD3 in OC.MethodsMicroarray data from GEO was used to analyze differential CpG sites and differentially methylated regions (DMR) in tumor tissues and Illumina 450 genome-wide methylation data was employed. The FOXD3 expression level was determined through qRT-PCR and western blot analysis. Wound healing test, colony formation and flow cytometry assay were utilized to analyze cell migration, proliferation abilities, cell cycle and cell apoptosis, respectively. Finally, the effect of FOXD3 on tumor growth was investigated through in vivo xenograft experiments.ResultsGEO data analysis showed that FOXD3 was hypermethylated in OC tissues. Also, qRT-PCR revealed that FOXD3 was low expressed and methylation-specific PCR (MSP) confirmed that the methylation level of FOXD3 was hypermethylated. Combined treatment of 5-aza-2′-deoxycytidine (5-Aza-dC) could synergistically restored FOXD3 expression. Finally, in vitro and in vivo experiments showed that demethylated FOXD3 decreased cell proliferation and migration abilities, and increased the cell apoptosis. In vivo experiment detected that demethylated FOXD3 restrained tumor growth.ConclusionsFOXD3 could act as a tumor suppressor to inhibit cell proliferation, migration and promote cell apoptosis in OC cells.
Highlights
FOXD3 is aberrantly regulated in several tumors, but its underlying mechanisms in ovarian cancer (OC) remains largely unknown
The cell cycle of FOXD3 overexpression group and demethylation group was significantly longer than that of control group (Fig. 7a–d). These findings suggest that FOXD3 could act as a tumor suppressor to inhibit cell proliferation, migration and promote cell apoptosis in OC cells
DNA methylation is a critical mechanism of gene silence and control of gene expression, which is associated with diverse regulation of cellular process [15]
Summary
FOXD3 is aberrantly regulated in several tumors, but its underlying mechanisms in ovarian cancer (OC) remains largely unknown. Since the association between aberrant DNA methylation patterns and malignancy was first found, its role in cancer development has been increasingly investigated [6]. DNA methyltransferases (DNMTs) could catalyze the adjunction of a methyl group to the cytosine ring to form methyl cytosine in which S-adenosylmethionine is recruited as a methyl donor [4]. Both the hypermethylation inducing the silence of tumor suppressor genes and hypomethylation associated with genomic instability have been involved in cancer initiation and tumor progression [7]. Aberrant methylation of CpG islands is a common epigenetic event occurred in EOC, which has the most variation type [8]. Investigation on variation of tumor DNA methylation contributes to better understand the mechanism of cancer
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