Correlation of Expression of Cyclooxygenase-2, Vascular Endothelial Growth Factor, and Peroxisome Proliferator–Activated Receptor δ With Head and Neck Squamous Cell Carcinoma

Abstract

Cyclooxygenase (COX) is the rate-limiting enzyme in the formation of prostaglandins from arachidonic acid. COX exists in 2 isoforms, COX-1 and COX-2. These isoforms are encoded by separate genes and demonstrate cell-specific expression and regulation. Peroxisome proliferator-activated receptor delta (PPARdelta) is a nuclear transcription factor that is activated by prostacyclin. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that is up-regulated in various tumors. Vascular endothelial growth factor has been shown to interact with COX-derived prostaglandins in angiogenesis. To better understand the roles of these genes in head and neck squamous cell carcinoma (HNSCCA), we examined the differential expression of the COX1, COX2, VEGF, and PPARdelta genes in these tumors. Tissue samples from patients with HNSCCA were analyzed for COX-1, COX-2, VEGF, and PPARdelta messenger RNAs (mRNAs) by in situ hybridization. COX-1 and COX-2 mRNAs were also evaluated with Northern blot hybridization. Immunohistochemistry was used to analyze for COX-2 and PPARdelta proteins. Results showed focal areas of accumulation for COX-2, VEGF, and PPARdelta but not COX-1 in human HNSCCA. Northern blot hybridization showed higher levels of COX-2 mRNA in HNSCCA than in normal tissue. This suggests a supportive role of COX-2 in development and/or progression of HNSCCA. In addition, PPARdelta may be a receptor for COX-2-produced prostaglandins in HNSCCA. There is a potential role for selective COX-2 inhibitors in the treatment of these lesions.

Curcumin down regulates smokeless tobacco-induced NF-κB activation and COX-2 expression in human oral premalignant and cancer cells

“…Our results are consistent with other studies which demonstrate that curcumin induced inhibition of cell survival and induction of apoptosis may be associated with the inhibition of PGE2 synthesis and down-regulation of COX-2 (Lev-Ari et al, 2006;Park et al, 2006). Additionally, it has been demonstrated that COX-2 is over-expressed in patients with head and neck cancer (Jaeckel et al, 2001), oral premalignant lesions and OSCCs (Banerjee et al, 2002;Shibata et al, 2005). Our observations suggest that expression of NF-B paralleled (and correlated with) COX-2 expression in clinical specimens of human oral premalignant lesions, leukoplakia, as early as in hyperplasia and remain elevated in dysplasia and down the carcinogenic pathway in oral squamous cell carcinomas as well.…”

Peroxisome proliferator‐activated receptors in squamous cell carcinoma and its precursors

“…Although the role of PPARb in tumor angiogenesis is not well documented, 18 this observation is in concert with a study in head and neck SCCs that suggested an association between vascular endothelial growth factor and PPARb. 17 In accordance with other studies that used immunohistochemistry, we demonstrated that if the expression of PPARa and PPARg was present, it was often confined to the basal layers, whereas the b subtype was also present in the suprabasal layers of the normal epidermis. 3,6,27 In AK and SCC, PPAR expression was more diffusely distributed.…”

Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A pathway

“…When using blockers of either cPLA 2 or COX-2 in cells exposed to high glucose we restored VEGF levels (both mRNA and protein), indicating that PG production is essential for VEGF to be induced by high glucose in pericytes. Consistent with our data, COX-2-derived PGE 2 has been reported to potently induce the angiogenic switch during mammary cancer progression [32], while other studies have shown a correlation of expression of COX-2 and VEGF in neoplastic tissues [33]. We cannot exclude, however, that also PG production from COX-1 takes part to the cell damage and VEGF expression induced by high glucose.…”