Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis.
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.
Lee
James J
JJ
Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Natsuizaka
Mitsuteru
M
Ohashi
Shinya
S
Wong
Gabrielle S
GS
Takaoka
Munenori
M
Michaylira
Carmen Z
CZ
Budo
Daniela
D
Tobias
John W
JW
Kanai
Michiyuki
M
Shirakawa
Yasuhiro
Y
Naomoto
Yoshio
Y
Klein-Szanto
Andres J P
AJ
Haase
Volker H
VH
Nakagawa
Hiroshi
H
D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D010100:Oxygen / Q000008:administration & dosage / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D053583:Interleukin-1beta; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D003035:Cobalt; D006911:Hydroxyprostaglandin Dehydrogenases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C018021:cobaltous chloride; D015232:Dinoprostone; D010100:Oxygen