当前位置： SCI文献检索 > CARCINOGENESIS期刊下所有文献 > Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis.

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

Abstract：

: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.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

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

doi

10.1093/carcin/bgp326

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

427-34

issue

eissn

0143-3334

issn

1460-2180

pii

bgp326

journal_volume

pub_type

杂志文章

在线工具

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