Journal Article

Targeted over-expression of mPGES-1 and elevated PGE<sub>2</sub> production is not sufficient for lung tumorigenesis in mice

Stacy A. Blaine, Amy M. Meyer, Greg Hurteau, Marilee Wick, Joseph A. Hankin, Robert C. Murphy, Andrew J. Dannenberg, Mark W. Geraci, Kotha Subbaramaiah and Raphael A. Nemenoff

in Carcinogenesis

Volume 26, issue 1, pages 209-217
Published in print January 2005 | ISSN: 0143-3334
Published online January 2005 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgh302
Targeted over-expression of mPGES-1 and elevated PGE2 production is not sufficient for lung tumorigenesis in mice

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There is a significant body of evidence suggesting that enzymes involved in arachidonic acid metabolism and their eicosanoid products play a role in various cancers, having both pro- and antitumorigenic effects. The goal of this study was to further define the role microsomal prostaglandin E synthases (mPGES-1) play in lung tumorigenesis. Transgenic mice were created with targeted over-expression of human mPGES-1 in the alveolar and airway epithelial cells using an SP-C promoter driven construct. Transgene positive (mPGES-1+) mice were shown to significantly over-express functional mPGES-1 in the lung and more specifically in alveolar type II cells. To study the effects of mPGES-1 over-expression in lung tumor formation, mice were exposed to a complete carcinogen protocol with a single injection of urethane or an initiation/promotion model with a single injection of 3-methylcholanthrene (MCA) followed by multiple injections of butylated hydroxytoluene (BHT). mPGES-1+ mice did not show a significant difference in tumor multiplicity or tumor size at 10, 16, 19 or 30 weeks after urethane injection compared with mPGES-1 mice. No significant difference was seen in tumor incidence, multiplicity or size at 19 weeks after treatment with MCA/BHT. Western blots verified that mPGES-1 expression was increased in tumors versus uninvolved tissue of both mPGES-1+ and mPGES-1 mice with overall expression being significantly higher in mPGES-1+ mice. Cyclooxygenase-2 levels were elevated in tumors in both groups. From these studies we conclude that over-expression of mPGES-1 and highly elevated PGE2 production are not sufficient to induce lung tumors.

Keywords: BHT, butylated hydroxytoluene; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; EIA, enzyme immunoassay; MCA, 3-methylcholanthrene; mPGES, microsomal prostaglandin E synthase; NSAIDs, non-steroidal antiinflammatory drugs; NSCLC, non-small cell lung cancer; PGI2, prostacyclin; PGIS, prostacyclin synthase

Journal Article.  6509 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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