Journal Article

Hypoxia-inducible factor-2α is essential in activating the COX2/mPGES-1/PGE<sub>2</sub> signaling axis in colon cancer

Xiang Xue and Yatrik M. Shah

in Carcinogenesis

Volume 34, issue 1, pages 163-169
Published in print January 2013 | ISSN: 0143-3334
Published online October 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs313
Hypoxia-inducible factor-2α is essential in activating the COX2/mPGES-1/PGE2 signaling axis in colon cancer

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

Cyclooxygenase 2 (COX2) is overexpressed in 80% of colon adenocarcinomas. However, the mechanism leading to aberrant COX2 expression in tumors is unclear. Intestinal epithelium-specific disruption of the von Hippel–Lindau tumor suppressor protein (VHL) in adenomatous polyposis coli (Apc)min/+ mice (VhlΔIE/Apcmin/+) resulted in constitutive activation of hypoxia-inducible factor (HIF), robustly enhanced colon carcinogenesis and potentiated COX2 expression in normal colon epithelium and tumors. In this study, we hypothesize that HIF regulates COX2 expression in colon tumors, and this regulation is critical for HIF-mediated colon carcinogenesis. COX2 was demonstrated to be a direct target gene of HIF-2α, and genetic disruption of HIF-2α abolished the induction of COX2 in tumors. Furthermore, inhibition of COX2 by nimesulide reduced HIF-2α-induced colon tumor formation. Interestingly, the levels of prostaglandin E2 (PGE2), the downstream effector of COX2, remained elevated in normal and tumor tissues of the nimesulide-treated VhlΔIE/Apcmin/+ mice. Further examination revealed that the terminal PGE2 synthesis enzyme microsomal prostaglandin E synthase 1 (mPGES-1) was overexpressed in the colon of VhlΔIE/Apcmin/+ mice. mPGES-1 was demonstrated to be a direct target gene of HIF-2α, and genetic disruption of HIF-2α abolished the induction of mPGES-1 in colon tumors. Together, our findings demonstrate that HIF-2α is a major regulator of COX2/mPGES-1/PGE2 pathway in colon tumors.

Journal Article.  4545 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.