VEGF expression is augmented by hypoxia‑induced PGIS in human fibroblasts

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Prostacyclin synthase (PGIS) converts prostaglandin H2 to prostaglandin I2 (PGI2).
• PGI2 promotes cancer growth via peroxisome proliferator-activated receptor δ (PPARδ) and increases vascular endothelial growth factor (VEGF).

Purpose of the Study:

• To investigate the role of PGIS in cellular responses to hypoxia.
• To elucidate the relationship between PGIS, VEGF, and PPARδ under hypoxic conditions.

Main Methods:

• Analyzing PGIS gene expression in human lung fibroblasts and cancer cells under hypoxia.
• Investigating PGIS localization changes using WI-38 cells.
• Measuring 6-keto-prostaglandin levels to confirm PGIS enzymatic activity.
• Utilizing PGIS and PPARδ knockdown (siRNA) to assess VEGF expression.

Main Results:

• Hypoxia enhanced PGIS expression and nuclear localization in WI-38 cells.
• Induced PGIS exhibited enzymatic activity, increasing 6-keto-prostaglandin levels.
• Hypoxia upregulated VEGF expression, which was dependent on PGIS and PPARδ.
• PGIS knockdown decreased VEGF mRNA levels, while PPARδ knockdown suppressed VEGF expression under hypoxia.

Conclusions:

• Hypoxia induces PGIS in fibroblasts, which in turn regulates VEGF expression.
• The PGIS-VEGF axis, modulated by PPARδ, plays a role in fibroblast-mediated tumor growth and angiogenesis.
• Fibroblasts in tumor hypoxic regions may contribute significantly to tumor progression.