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

Abstract

Purpose: Prostaglandin E 2 (PGE 2 ) promotes malignant growth. Cyclooxygenase (COX) catalyzes the synthesis of PGH 2 , which is converted, in turn, by microsomal prostaglandin E synthase (mPGES-1) to PGE 2 . One strategy for inhibiting carcinogenesis is to prevent PGE 2 production in premalignant and malignant tissues. It is important, therefore, to determine whether enzymes involved in PGE 2 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 PGE 2 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. PGE 2 and all four of the PGE 2 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.

Chemotherapy Induces the Expression of Cyclooxygenase-2 in Non–Small Cell Lung Cancer

“…Previous studies have shown that levels of COX-2 and PGE 2 are commonly increased in different tumor types (7 -19, 40 -43). Generally, the magnitude of these increases is quite variable both within and between tumor types (8,11,13,39). The current findings imply that intratumoral levels of COX-2 and prostanoids need to be interpreted in the context of whether cytotoxic therapy was given before tissue acquisition.…”

“…This was carried out using methods that have been reported previously (39). Neutral buffered formalin-fixed tissue was embedded in paraffin.…”

Celecoxib promotes degranulation of CD8+ T cells in HPV-induced lesions of K14-HPV16 transgenic mice

“…COX-2 is an enzyme with an imperative role in the metabolism of arachidonic acid, which leads to the production of prostaglandins, which in turn promote inflammation [32]. In fact, COX-2 is over-expressed in several malignancies, including cervical cancer [33][34][35][36][37]. As inflammation is known to contribute for cancer progression [31], COX-2 inhibition is expected to result in tumour growth inhibition whilst reducing inflammation.…”

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

“…Induction of mPGES-1 expression and its function have been observed in various diseases and systems in which COX-2-driven PGE 2 has been implicated, such as rheumatoid arthritis, febrile response, reproduction, bone metabolism, cardiovascular function, stroke and Alzheimer's disease (Kamei et al, 2004;Samuelsson et al, 2007;Hara et al, 2010). It has also been reported that mPGES-1 is constitutively expressed in several cancers, most of which also express COX-2 constitutively (Kamei et al, 2003;Golijanin et al, 2004). We have reported that the forcible transfection of mPGES-1 in combination with COX-2, but not with COX-1, into HEK293 cells led to cellular transformation, with a concomitant and robust increase in PGE 2 (Kamei et al, 2003).…”