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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

Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, Faculty of Medical and Veterinary Science, University Bristol, Bristol, United Kingdom

Requests for reprints: Christos Paraskeva, Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, Faculty of Medical and Veterinary Science, Bristol University, BS8 1TD, Bristol, United Kingdom. Phone: 117-928-7894; Fax: 117-928-7896; E-mail: c.paraskeva{at}bristol.ac.uk.

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 microenvironmental 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 induction. Oligonucleotide pull-down and chromatin immunoprecipitation assays reveal that HIF-1 binds a hypoxia-responsive element on the COX-2 promoter. COX-2 up-regulation during hypoxia is accompanied by increased levels of prostaglandin E₂ (PGE₂), which promote tumor cell survival under hypoxic conditions. In addition, elevated levels of PGE₂ 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. (Cancer Res 2006; 66(13): 6683-91)

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