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Carcinogenesis Advance Access published online on October 7, 2004
Carcinogenesis, doi:10.1093/carcin/bgh302
© 2004 by Oxford University Press
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Received July 1, 2004
Revised September 28, 2004
Accepted September 29, 2004

CARCINOGENESIS

Targeted overexpression of mPGES-1 and elevated PGE2 production is not sufficient for lung tumorigenesis in mice

Stacy A. Blaine 1, Amy M. Meyer 2, Greg Hurteau 2, Marilee Wick 2, Joseph A. Hankin 3, Robert C. Murphy 4, Kotha Subbaramaiah 5, Andrew J. Dannenberg 5, Mark W. Geraci 2, and Raphael A. Nemenoff 6*

1 Department of Pharmacology, University of Colorado Health Science Center, Denver, CO 80262
2 Department of Medicine, University of Colorado Health Science Center, Denver, CO 80262
3 Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206
4 Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206; Department of Pharmacology, University of Colorado Health Science Center, Denver, CO 80262
5 Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021
6 Department of Medicine, University of Colorado Health Science Center, Denver, CO 80262; Department of Pharmacology, University of Colorado Health Science Center, Denver, CO 80262

* To whom correspondence should be addressed. E-mail: raphael.nemenoff{at}uchsc.edu.


  Abstract

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 anti-tumorigenic effects. The goal of this study was to further define the role mPGES-1 plays in lung tumorigenesis. Transgenic mice were created with targeted overexpression 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 overexpress functional mPGES-1 in the lung and more specifically in alveolar type II cells. To study the effects of mPGES-1 overexpression 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 MCA followed by multiple injections of 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 to 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. COX-2 levels were elevated in tumors in both groups. From these studies we conclude that overexpression of mPGES-1 and highly elevated PGE2 production are not sufficient to induce lung tumors.


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