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Lee JJ , Natsuizaka M , Ohashi S , Wong GS , Takaoka M , Michaylira CZ , Budo D , Tobias JW , Kanai M , Shirakawa Y , Naomoto Y , Klein-Szanto AJP , Haase VH , Nakagawa H
Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis
Carcinogenesis. 2010 Mar;31(3) :427-434
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Hypoxia-inducible factors (HIFs), in particular HIF-1 alpha, 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-1 alpha 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-1 alpha by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1 alpha. 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-1 alpha-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-1 alpha and IGFBP3. Activation of the COX-2-PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1 beta and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1 alpha 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.
Lee, James J. Natsuizaka, Mitsuteru Ohashi, Shinya Wong, Gabrielle S. Takaoka, Munenori Michaylira, Carmen Z. Budo, Daniela Tobias, John W. Kanai, Michiyuki Shirakawa, Yasuhiro Naomoto, Yoshio Klein-Szanto, Andres J. P. Haase, Volker H. Nakagawa, Hiroshi Oxford univ press Oxford 564ve