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Prostacyclin in Human Non-small Cell Lung Cancers* FREE TO VIEW

Patrick Nana-Sinkam, MD; Heiko Golpon, MD; Robert L. Keith, MD; Ryan J. Oyer, MS; Sylk Sotto-Santiago, MBA; Mark D. Moore, BS; Wilbur Franklin, MD; Raphael A. Nemenoff, PhD; Mark W. Geraci, MD
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*From the Division of Pulmonary Sciences and Critical Care Medicine (Drs. Nana-Sinkam, Golpon, Keith, and Geraci, and Messrs. Oyer, Sotto-Santiago, and Moore), Division of Nephrology (Dr. Nemenoff), and Department of Pathology (Dr. Franklin), University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Patrick Nana-Sinkam, MD, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East 9th Ave, Box C272, Denver, CO 80262; e-mail: patrick.nana-sinkam@uchsc.edu

Chest. 2004;125(5_suppl):141S. doi:10.1378/chest.125.5_suppl.141S
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Lung cancer is the leading cause of cancer death in men and women in the United States. The cyclooxygenase pathway has a role in colon cancer chemoprevention and a potential role in lung cancer. Cyclooxygenase inhibition reduces lung cancer multiplicity in a murine model. We have shown that prostacyclin synthase (PGI2S) overexpression protects against tumor development in a transgenic mouse model. We hypothesize that eicosanoid balance is of importance in lung tumorigenesis, and propose a model for transcriptional regulation of PGI2S.

PGI2S expression in human non-small cell lung cancer samples and normal lung was evaluated by the following: (1) immunohistochemistry, (2) quantitative polymerase chain reaction, (3) Western analysis, and (4) eicosanoid levels of 6-keto prostaglandin F1 (PGF1)-α (the stable metabolite of prostacyclin) and prostaglandin E2 (PGE2) The 3-kilobase region of the prostacyclin synthase promoter as well as truncated constructs were placed into a luciferase construct and transfected into cell lines. The construct was then exposed to platelet-derived growth factor and co-transfected with constitutively active H-Ras.

Tumors produced very low levels of 6-keto PGF1-α, decreased PGI2S messenger RNA, and decreased PGI2S protein expression by immunohistochemistry when compared to normal surrounding lung tissue. However, tumors produced high levels of PGE2. Luciferase reporter constructs demonstrate that maximal PGIS transcriptional activity resides in the first 183 base-pairs upstream from the start codon. Furthermore, a number of functional polymorphisms in the promoter region are related to the variable number tandem repeats in the promoter region. Lastly, PGI2S is negatively regulated by H-Ras and platelet-derived growth factor.

Assays for the prostacyclin metabolite and PGE2, quantitative polymerase chain reaction, Western analysis, and immunohistochemistry all suggest an association between prostacyclin and human non-small cell lung cancer. Furthermore, a balance of 6-keto PGF1α and PGE2 is likely of importance. In further studies, tumors will be evaluated by tissue microarray to determine the following: (1) whether the relative absence of PGI2S is associated with lung tumors of various histologies, and (2) whether PGI2S may serve as a marker of tumor aggressiveness or survival. Studies are in progress to define the regulation of PGI2S by other growth factors such as vascular endothelial growth factor, to elucidate the signaling mechanisms, and to determine physiologic effects of PGI2S on cell proliferation.

Abbreviations: PGE2 = prostaglandin E2; PGF1 = prostaglandin F1; PGI2S = prostacyclin synthase




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