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Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Are Overexpressed in Squamous Cell Carcinoma of the Penis

¹ Departments of Urology and ² Surgery, Memorial Sloan-Kettering Cancer Center, New York; ³ Department of Otolaryngology, North Shore-Long Island Jewish Research Institute, Albert Einstein College of Medicine, Manhasset; and Departments of ⁴ Medicine and ⁵ Pathology, Weill Medicine College of Cornell University and Strang Cancer Prevention Center, New York, New York

Purpose: Prostaglandin E₂ (PGE₂) promotes malignant growth. Cyclooxygenase (COX) catalyzes the synthesis of PGH₂, which is converted, in turn, by microsomal prostaglandin E synthase (mPGES-1) to PGE₂. One strategy for inhibiting carcinogenesis is to prevent PGE₂ production in premalignant and malignant tissues. It is important, therefore, to determine whether enzymes involved in PGE₂ biosynthesis are deregulated in neoplasia. The main purpose of this study was to determine whether amounts of COX-2 or mPGES-1 were increased in intraepithelial neoplasia or squamous cell carcinoma (SCC) of the penis. Because human papillomavirus (HPV) has been linked to the development of penile SCC, a secondary objective was to determine whether COX-2 was overexpressed in SCC arising in an HPV16 transgenic mouse.

Experimental Design: Immunohistochemistry and immunoblotting were used to evaluate the expression of COX-2 and mPGES-1 in benign and malignant lesions including metastases to lymph nodes. Amounts of intratumoral PGE₂ were quantified by enzyme immunoassay. Reverse transcription-PCR was used to determine the expression of each of the four known receptors (EP_1–4) for PGE_2.

Results: Immunohistochemistry demonstrated increased expression of COX-2 and mPGES-1 in dysplasia, carcinoma in situ, invasive SCC, and metastases to lymph nodes. Immunoblot analysis confirmed that COX-2 and mPGES-1 were consistently overexpressed in SCC. PGE₂ and all four of the PGE₂ receptor subtypes were detected in each of the tumor samples. Elevated levels of COX-2 were also detected in SCC arising in an HPV16 transgenic mouse.

Conclusions: Increased amounts of COX-2 and mPGES-1 were detected in penile intraepithelial neoplasia and carcinoma. These findings provide the basis for evaluating whether inhibiting COX-2 will be useful in the prevention or treatment of penile SCC.

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