Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia

被引：250

作者：

Kaidi, Abderrahmane ^{[1
]}

Qualtrough, David ^{[1
]}

Williams, Ann C. ^{[1
]}

Paraskeva, Christos ^{[1
]}

机构：

[1] Univ Bristol, Fac Med & Vet Sci, Dept Cellular & Mol Med, Canc Res UK,Colorectal Tumor Biol Res Grp, Bristol BS8 1TD, Avon, England

来源：

CANCER RESEARCH | 2006年 / 66卷 / 13期

关键词：

D O I：

10.1158/0008-5472.CAN-06-0425

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Cyclooxygenase (COX)-2, the inducible key enzyme for prostanoid biosynthesis, is overexpressed in most colorectal carcinomas and a subset of colorectal adenomas. Genetic, biochemical, and clinical evidence indicates an important role for COX-2 in colorectal tumorigenesis. Although COX-2 can be induced by aberrant growth factor signaling and oncogene activation during colorectal tumorigenesis, the role of micro-environmental factors such as hypoxia in COX-2 regulation remains to be elucidated. For the first time, we report that under hypoxic conditions COX-2 protein levels increase in colorectal adenoma and carcinoma cells. Rigorous analyses reveal that COX-2 up-regulation is transcriptional and is associated with hypoxia-inducible factor (HIF)-1 alpha. induction. Oligonucleotide pull-down and chromatin immunoprecipitation assays reveal that HIF-1 alpha binds a hypoxia-responsive element on the COX-2 promoter. COX-2 up-regulation during hypoxia is accompanied by increased levels of prostaglandin E-2 (PGE(2)), which promote tumor cell survival under hypoxic conditions. In addition, elevated levels of PGE(2) in hypoxic colorectal tumor cells enhance vascular endothelial growth factor expression and HIF-1 transcriptional activity by activating the mitogen-activated protein kinase pathway, showing a potential positive feedback loop that contributes to COX-2 up-regulation during hypoxia. This study identifies COX-2 as a direct target for HIF-1 in colorectal tumor cells. In addition, COX-2 up-regulation represents a pivotal cellular adaptive response to hypoxia with implication for colorectal tumor cell survival and angiogenesis. We propose that using modified COX-2-selective inhibitors, which are only activated under hypoxic conditions, could potentially be a novel more selective strategy for colorectal cancer prevention and treatment.

引用

页码：6683 / 6691

页数：9