Aberrant DNA Methylation-Mediated FOXF2 Dysregulation Is a Prognostic Risk Factor for Gastric Cancer

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.

Aberrant Methylation of the Imprinted C19MC and MIR371-3 Clusters in Patients with Non-Small Cell Lung Cancer

“…For example, according to our results, decreased FOXF2 expression has been reported as an independent predictor of poor prognosis for patients with early-stage NSCLC [76]. FOXF2 deregulation ought to an aberrant DNA methylation status has also recently been identified for gastric cancer [77]. In the case of MICA, Okita et al reported that PD-L1 low /MICA/B high is associated with a better clinical outcome in patients with stage I-IIIA NSCLC.…”

Prognostic significance of JAM 3 in gastric cancer: An observational study from TCGA and GEO

“…More and more corroboration alludes to a crucial role for aberrant DNA methylation in the initiation and development of GC. [25][26][27][28] To begin our investigation, we used Pearson coefficients to see if the JAM3 methylation status affected JAM3 mRNA expression. In GC tissues, a strong inverse connection was seen between JAM3 methylation and JAM3 mRNA expression.…”

FOXF2 Regulates PRUNE2 Transcription in the Pathogenesis of Colorectal Cancer

“…FOXF2 is mainly expressed in the epithelial–mesenchymal cells of the respiratory tract, digestive tract, urinary tract, and other organs and is involved in extracellular matrix synthesis, mutual transformation between the epithelium and mesenchymal tract, and embryonic and tissue development. 8 – 10 FOXF2 is correlated with tumor progression, metastasis of breast cancer, 11 , 12 lung cancer, 13 – 15 hepatocellular carcinoma (HCC), 16 , 17 colorectal cancer (CRC), 18 – 22 prostate cancer (PC), 23 – 25 gastric cancer (GC), 26 , 27 oral cancer, 28 ovarian cancer (OC), 29 mouse rhabdomyosarcoma, 30 bladder cancer, 31 and esophageal squamous cell carcinoma. 32 FOXF2 has shown inhibitory effects in most tumors, such as liver cancer 16 , 17 and prostate cancer, 25 and shown tumor-promoting effects in lung cancer 14 and mouse rhabdomyosarcoma.…”