ArticleScientific reports2025
Epigenetic modulation of VEGF-A/VEGFR2 pathway genes in OC/TME axis driving genetic upregulation and tumor plasticity.
Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Tumor heterogeneity has been recognized as a critical characteristic of Ovarian Cancer (OC), significantly influencing chemotherapeutic response and overall patient survival. The VEGF/VEGFR2 signaling pathway genes serve as risk factor for metastasis and are associated with poor prognosis in many cancers including OC. DNA methylation of VEGF-A, VEGF-C and VEGFR2 genes contributing to their genetic changes based on histological sub-types has not been thoroughly explored in OC. Thus, the study aimed to determine the DNA methylation status of these genes in relation to their expression in tumor tissues and associated peritoneal fluid samples to evaluate usefulness of methylation as a prognostic indicator in ovarian carcinoma for future targeted therapies. Bisulfite-modified DNA methylation was assessed via Methylation-Specific Polymerase chain reaction (MSP) and mRNA expression was examined via quantitative reverse transcription PCR (RT-PCR), respectively. Gene expression and promoter methylation were examined in relation with clinical parameters in 100 OC samples. The methylation frequency of VEGF-A, VEGF-C and VEGFR2 promoters was higher in tumor tissues and matched Peritoneal Fluid (PF) compared to normal samples, while VEGF-A, VEGF-C and VEGFR2 mRNA expression levels were significantly elevated. Promoter methylation levels for VEGF-A (82%), VEGF-C (76%) and VEGFR2 (82%) showed significantly higher levels compared to benign cystadenomas, whereas amounts of VEGF-A and VEGFR2 were significantly higher than benign samples (p = 0.0003 and 0.001). Expression and promoter methylation for VEGF-A (p = 0.0004, 0.0001) and VEGFR2 (p = 0.005, 0.001) significantly correlated with differences in histological sub-types in OC samples. No significant correlation was observed between promoter methylation and expression levels for VEGF-A, VEGF-C and VEGFR2 genes. Kaplan-Meier survival analysis predicts poor prognosis for concurrent high expression and methylation of VEGF-A and VEGFR2 significantly correlated with advanced stage (log-rank p = 0.03, 0.01) and tumor histology (log rank p = 0.02, 0.01 respectively) in OC patients. Promoter methylation status of the VEGF-A and VEGFR2 genes could serve as valuable prognostic indicator in predicting poor prognosis in OC patients based on tumor histological sub-types.
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