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<p><i>Vascular Endothelial Growth Factor A (VEGFA)</i> is a critical regulatory gene involved in cellular proliferation, neovascularisation, and tumorigenic progression in solid tumors. Upregulation of <i>VEGFA</i> transcription is initiated upon the binding of Hypoxic Inducible Factor-1 (HIF-1α and HIF-1β) heterodimer to the Hypoxic Responsive Element (HRE) on the <i>VEGFA</i> gene within the hypoxic tumor microenvironment. Consequently, disruptions of the HIF-1 heterodimer interactions and the HRE cognate on the <i>VEGFA</i> gene should prevent its transcription in tumors. Herein, we demonstrated sequence-specific targeting of <i>VEGFA</i> genomic DNA using next-generation gamma-modified Peptide Nucleic Acid (γPNA) to prevent HIF-1 interaction and silence <i>VEGFA</i> expression in a series of solid cancer cell lines and in vivo studies. The efficacy of γPNA1 targeting genomic <i>VEGFA</i> in multiple solid tumor cell lines was confirmed through gene expression analysis, Western blot analysis, and cell viability-based functional studies. Preclinical testing in xenograft mouse models of triple-negative breast cancer (TNBC) demonstrated that targeting <i>VEGFA</i> genomic DNA resulted in a notable decrease in tumor growth and an increase in survival rates in mice. In this study, we established a therapeutic approach for precisely targeting <i>VEGFA</i> genomic DNA to suppress its transcription and control tumor progression.</p><p></p>

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Sequence-specific targeting of VEGFA genomic DNA to inhibit tumor growth

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Angana De,
  • Sai Pallavi Pradeep,
  • Paroma Deb,
  • Ravinder Reddy Gaddam,
  • Ajit Vikram,
  • Raman Bahal

摘要

Vascular Endothelial Growth Factor A (VEGFA) is a critical regulatory gene involved in cellular proliferation, neovascularisation, and tumorigenic progression in solid tumors. Upregulation of VEGFA transcription is initiated upon the binding of Hypoxic Inducible Factor-1 (HIF-1α and HIF-1β) heterodimer to the Hypoxic Responsive Element (HRE) on the VEGFA gene within the hypoxic tumor microenvironment. Consequently, disruptions of the HIF-1 heterodimer interactions and the HRE cognate on the VEGFA gene should prevent its transcription in tumors. Herein, we demonstrated sequence-specific targeting of VEGFA genomic DNA using next-generation gamma-modified Peptide Nucleic Acid (γPNA) to prevent HIF-1 interaction and silence VEGFA expression in a series of solid cancer cell lines and in vivo studies. The efficacy of γPNA1 targeting genomic VEGFA in multiple solid tumor cell lines was confirmed through gene expression analysis, Western blot analysis, and cell viability-based functional studies. Preclinical testing in xenograft mouse models of triple-negative breast cancer (TNBC) demonstrated that targeting VEGFA genomic DNA resulted in a notable decrease in tumor growth and an increase in survival rates in mice. In this study, we established a therapeutic approach for precisely targeting VEGFA genomic DNA to suppress its transcription and control tumor progression.