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Epidermal Growth Factor–Induced Cyclooxygenase-2 Expression Is Mediated through Phosphatidylinositol-3 Kinase, Not Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase, in Recurrent Respiratory Papillomas

Authors' Affiliations: ¹ Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York; ² Department of Otolaryngology and Communicative Disorders, Long Island Jewish Medical Center, New Hyde Park, New York; and ³ Department of Medicine, Weill Medical College of Cornell University, New York, New York

Requests for reprints: Rong Wu, Department of Otolaryngology and Communicative Disorders, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY 11040. Phone: 718-470-7669; E-mail: rwu1{at}lij.edu.

Purpose: Recurrent respiratory papillomas, caused by human papillomaviruses, are premalignant tumors that overexpress the epidermal growth factor receptor (EGFR). The goals of this study were as follows: (a) to evaluate the expression of cyclooxygenase-2 (COX-2) in papillomas, (b) to investigate the role of EGFR signaling in COX-2 expression, and (c) to determine whether COX-2 activity is important for the growth of papilloma cells.

Experimental Design: Immunohistochemistry, Western blotting, and real-time PCR were used to determine levels of COX-2 in papilloma and normal laryngeal tissue. Explant cultures of both normal laryngeal and papilloma cells were used to define the signaling pathways that regulate COX-2 expression and investigate the potential of targeting COX-2 as a strategy to suppress papilloma growth.

Results: COX-2 levels were markedly increased in papillomas. In vitro studies suggested that overexpression in papillomas reflected activation of EGFRphosphatidylinositol 3-kinase signaling. Treatment with prostaglandin E₂ (PGE₂) induced COX-2, whereas celecoxib, a selective COX-2 inhibitor, suppressed levels of COX-2, suggesting a positive feedback loop. Moreover, treatment with PGE₂ stimulated papilloma cell growth, whereas celecoxib suppressed proliferation and induced apoptosis.

Conclusions: Overexpression of COX-2 in papillomas seems to be a consequence of enhanced EGFRphosphatidylinositol 3-kinase signaling. We propose a positive feedback loop for COX-2 expression, with induction of COX-2 resulting in enhanced PGE₂ synthesis and further expression of COX-2 that contributes to the growth of papillomas in vivo. These data strengthen the rationale for evaluating whether nonsteroidal anti-inflammatory drugs, prototypic COX inhibitors, will be useful in the management of respiratory papillomas.

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