Epigenetic modulation of VEGF-A/VEGFR2 pathway genes in OC/TME axis driving genetic upregulation and tumor plasticity

Sep 24, 2026

Tumor heterogeneity is a key feature of ovarian cancer (OC), affecting chemotherapy response and patient survival. The VEGF/VEGFR2 signaling pathway supports metastasis and poor prognosis, yet DNA methylation changes of VEGF-A, VEGF-C, and VEGFR2 across histological subtypes in OC remain insufficiently characterized. This study evaluates bisulfite-modified methylation by MSP and mRNA by quantitative RT-PCR in 100 tumor and matched peritoneal fluid samples, linking promoter methylation with expression, clinical parameters, and survival outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

Study Aim and Rationale

Methods (MSP and RT-PCR)

Key Findings

Clinical Correlations and Survival Analysis

Keywords

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Epigenetic modulation of VEGF-A/ VEGFR2 pathway genes inOC/TME axis driving genetic upregulation and tumor plasticity Abida Bhat1, Yasir Bashir2,6, Abdul Basit Baba2,6, Sadaf Dar2, Sheikh Zahoor Ahmad3, Syed Besina Yasin4, Ab Wahid Mir3, Syed NisarAhmad5, Tahira Yousuf1 & DilAfroze1,2,6􀀍 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 inOC. 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. Bisulfitemodified 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-Cand 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. Keywords OC (ovarian cancer), PF (peritoneal fluid), VEGF (vascular endothelial growth factor), VEGFR2 (vascular endothelial growth receptor 2), TCGA (The Cancer genome Atlas), MSP (Methylation specific PCR), TME (Tumor Microenvironment) Ovarian cancer (OC) is a leading cause of female mortality, largely due to ineffective early-stage detection. In 2020, OC was projected to cause 313,959 new cases and 207,252 deaths globally, with an incidence rate of 6.6/100,000 and a fatality rate of 4.2/100,0001. The highest mortality rates are in low-and middle-income countries such as India, where OC is among the top ten cancers, with cases expected to rise from 43,886 in 1Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu & Kashmir, India. 2Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Soura, Jammu & Kashmir, India. 3Department of Surgical Oncology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Jammu & Kashmir, India. 4Department of Pathology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Jammu & Kashmir, India. 5Department of Medical Oncology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Jammu & Kashmir, India. 6Yasir Bashir, Abdul Basit Baba, Sheikh Za

FAQs

What genes and pathway are examined in this study?

The study focuses on DNA methylation and mRNA expression of VEGF-A, VEGF-C, and VEGFR2, within the VEGF/VEGFR2 signaling context in ovarian cancer.

How were DNA methylation and gene expression measured?

DNA methylation was assessed using bisulfite-modified DNA with methylation-specific PCR (MSP). mRNA expression was measured using quantitative reverse transcription PCR (RT-PCR).

Do promoter methylation levels correlate with mRNA expression in OC?

No significant correlation was observed between promoter methylation and expression levels for VEGF-A, VEGF-C, and VEGFR2.

What is the prognostic relevance of VEGF-A and VEGFR2 promoter methylation?

Kaplan–Meier survival analysis indicates poor prognosis when VEGF-A and VEGFR2 show concurrent high expression and methylation, which also aligns with advanced stage and tumor histology.

Sep 24, 2026

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