Abstract
Background: The prognosis of gastric cancer (GC) patients is poor. The effect of aberrant DNA methylation on FOXF2 expression and the prognostic role of FOXF2 methylation in GC have not yet been identified.Methods: The RNA-Seq and gene methylation HM450 profile data were used for analyzing FOXF2 expression in GC and its association with methylation level. Bisulfite sequencing PCR (BSP) was performed to measure the methylation level of the FOXF2 promoter region in GC cell lines and normal GES-1 cells. The cells were treated with the demethylation reagent 5-Aza-dC, and the mRNA and protein expression levels of FOXF2 were then measured by qRT-PCR and western blot assays. The risk score system from SurvivalMeth was calculated by integrating the methylation level of the cg locus and the corresponding Cox regression coefficient.Results: FOXF2 was significantly downregulated in GC cells and tissues. On the basis of RNA-Seq and Illumina methylation 450 data, FOXF2 expression was significantly negatively correlated with the FOXF2 methylation level (Pearson’s R = −0.42, p < 2.2e−16). The FOXF2 methylation level in the high FOXF2 expression group was lower than that in the low FOXF2 expression group. The BSP assay indicated that the methylation level of the FOXF2 promoter region in GC cell lines was higher than that in GES-1 cells. The qRT-PCR and western blot assay showed that FOXF2 mRNA and protein levels were increased in GC cells following treatment with 5-Aza-Dc. The methylation risk score model indicated that patients in the high risk group had poorer survival probability than those in the low risk group (HR = 1.84 (1.11–3.07) and p = 0.0068). FOXF2 also had a close transcriptional regulation network with four miRNAs and their corresponding target genes. Functional enrichment analysis of the target genes revealed that these genes were significantly related to several important signaling pathways.Conclusion: FOXF2 was downregulated due to aberrant DNA methylation in GC, and the degree of methylation in the promoter region of FOXF2 was related to the prognosis of patients. The FOXF2/miRNAs/target genes axis may play a vital biological regulation role in GC.
Highlights
Gastric cancer (GC) remains an important cancer worldwide, with a large number of new cases and deaths each year, making it the fifth most frequently diagnosed cancer and the third leading cause of cancer-related deaths (Bray et al, 2018)
Forkhead box F2 (FOXF2) is Downregulated in GC Cells and Tissues
Three expression profiling data from GEO datasets showed that FOXF2 was down-regulated in GC tissues (Figure 1C)
Summary
Gastric cancer (GC) remains an important cancer worldwide, with a large number of new cases and deaths each year, making it the fifth most frequently diagnosed cancer and the third leading cause of cancer-related deaths (Bray et al, 2018). Other risk factors include high salt diet, low-fruit diet, drinking, and smoking (IARC, 2012). Epigenetic dysregulation plays an indispensable role in the development and progression of GC (Ebrahimi et al, 2020). In addition to changes and mutations in the genomic DNA sequence, epigenetic changes are observed in the mechanisms of gene expression regulation, including DNA methylation, chromatin remodeling, alteration in noncoding RNA expression, and histone post-translational modifications, and these changes are reversible (Puneet et al, 2018). Aberrant methylation of the CpG island in the promoter region of the gene plays an important role in its inactivation. Abnormal methylation of the CpG island in the promoter region of the tumor suppressor gene leads to its transcriptional inhibition, downregulation, or deletion of expression, resulting in the development of GC. The effect of aberrant DNA methylation on FOXF2 expression and the prognostic role of FOXF2 methylation in GC have not yet been identified
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