Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hypoxia-inducible factors (HIFs), particularly HIF-1alpha, play a significant role in tumor biology.
• Identifying HIF target genes within the esophageal tumor microenvironment is crucial for understanding tumor progression.

Purpose of the Study:

• To identify novel HIF target genes in the esophageal tumor microenvironment.
• To investigate the role of prostaglandin E synthase (PTGES) in esophageal squamous cell carcinoma (ESCC) under hypoxic conditions.

Main Methods:

• Gene expression profiling of hypoxia-exposed esophageal epithelial cells (EPC2-hTERT) compared to ESCC gene signatures.
• Validation of PTGES as a HIF-1alpha target gene using hypoxia, cobalt chloride, and dominant-negative HIF-1alpha.
• Assessment of Prostaglandin E2 (PGE2) biosynthesis and PTGES expression in ESCC cells and primary tumors.

Main Results:

• Prostaglandin E synthase (PTGES) was identified as a novel HIF-1alpha target gene, upregulated in ESCC and hypoxia-exposed cells.
• PTGES induction was dependent on HIF-1alpha stabilization and regulated at both mRNA and protein levels.
• Hypoxia stimulated PGE2 production in a HIF-1alpha-dependent manner, and PTGES was frequently overexpressed in ESCC.

Conclusions:

• PTGES is a novel HIF-1alpha target gene involved in prostaglandin E biosynthesis within the hypoxic esophageal tumor microenvironment.
• The COX-2-PTGES axis is activated in ESCC, suggesting its potential role in tumor progression.
• Findings have implications for understanding and potentially targeting hypoxic microenvironments in various tumor types, especially squamous cell carcinomas.