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

Lee JJ, Natsuizaka M, Ohashi S, Wong GS, Takaoka M, Michaylira CZ, Budo D, Tobias JW, Kanai M, Shirakawa Y, Naomoto Y, Klein-Szanto AJ, Haase VH, Nakagawa H
Carcinogenesis. 2010 31 (3): 427-34

PMID: 20042640 · PMCID: PMC2832548 · DOI:10.1093/carcin/bgp326

Hypoxia-inducible factors (HIFs), in particular HIF-1alpha, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1alpha target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1alpha by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1alpha. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E(2) (PGE(2)) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE(2) production in a HIF-1alpha-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1alpha and IGFBP3. Activation of the COX-2-PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1beta and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1alpha target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin.

MeSH Terms (26)

Carcinoma, Squamous Cell Cell Hypoxia Cell Line Cobalt Cyclooxygenase 2 Dinoprostone Enzyme Activation Epithelial Cells Esophageal Neoplasms Gene Expression Profiling Humans Hydroxyprostaglandin Dehydrogenases Hypoxia-Inducible Factor 1, alpha Subunit Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor Binding Proteins Interleukin-1beta Intramolecular Oxidoreductases Neoplasm Proteins Oxygen Prostaglandin-E Synthases Recombinant Fusion Proteins RNA, Messenger RNA, Neoplasm RNA, Small Interfering RNA Interference Tumor Cells, Cultured

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