Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Y-box binding protein-1 (YB-1) is overexpressed in cancer cells and tumor vasculature, contributing to cancer progression and treatment resistance.
• Targeting YB-1 presents a potential strategy for antiangiogenic cancer therapy.

Purpose of the Study:

• To investigate the therapeutic potential of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB-1 ASO^A) for antiangiogenic cancer therapy.
• To compare the efficacy and safety of YB-1 ASO^A with other ASO modifications.

Main Methods:

• Administration of YB-1 ASO^A via intravenous injection in a xenograft tumor model.
• Assessment of YB-1 expression in tumor endothelial and cancer cells.
• Evaluation of downstream signaling pathways, including Bcl-xL/VEGFR2 and Bcl-xL/Tie.
• Analysis of tumor growth and expression of angiogenesis markers (VEGFR2, Tie2).
• Assessment of liver function to evaluate safety.

Main Results:

• YB-1 ASO^A demonstrated superior knockdown efficiency and safety compared to DNA-based ASOs and locked nucleic acid (LNA)-modified ASOs.
• YB-1 ASO^A significantly inhibited YB-1 expression in tumor angiogenic endothelial cells.
• The therapy downregulated Bcl-xL/VEGFR2 and Bcl-xL/Tie signaling axes, inducing apoptosis in vascular endothelial cells.
• YB-1 ASO^A suppressed tumor growth in a xenograft model, decreasing VEGFR2 and Tie2 expression in tumor vessels.

Conclusions:

• The YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signaling pathways are critical for tumor angiogenesis.
• YB-1 ASO^A exhibits significant antiangiogenic and antitumor effects, suggesting its feasibility as a therapeutic agent for solid tumors.