Summary:
Introduction: Cyclooxygenase-2 (COX-2), a critical enzyme in the conversion of
arachidonic acid to prostaglandin E2, influences the biological behavior of
human tumors, being involved in carcinogenesis, tumor progression, reduced
apoptosis and differentiation. Peroxisome Proliferator-Activated Receptor γ
(PPARγ) is a ligand –activated transcriptional factor with anti-proliferative
and anti-tumoral effects. Although COX-2 and PPARγ have been implicated in the
progression of various human cancers, their expression in bladder cancer has
not been addressed.
Methods: Immunohistochemistry (ABC-HRP method) and image analysis were
performed to detect expression of COX-2 and PPARγ in 134 urothelial bladder
carcinomas. To assess their role in bladder cancer, their expression was
evaluated in relation to known clinicopathologic parameters (grade and stage),
markers of apoptotic potential and differentiation (caspase-3, bax-protein,
MLH1, hTERT and Ki-67) and patients’ overall survival. Statistical analysis was
univariate and multivariate.
Results: Immunoreactivity for COX-2 and PPARγ was observed in the cytoplasm
and in the nucleus of cancer cells in 70.1% and 78.6% of samples respectively.
COX-2 expression was unrelated to tumor grade and local invasion but it was
positively linked with caspase-3, bax-protein and MLH1 (p=0.007, p=0.026 and
p=0.019 respectively), and inversely correlated to hTERT (p=0.009). COX-2
immunopositivity was independently associated with worse prognosis of patients
with non-muscle invasive urothelial carcinomas (p=0.002). PPARγ expression was
inversely associated with stage (p<0.001), tumor grade (p=0.002) and the
expression of Ki-67 (p=0.042), while it was found to exert a favorable effect
on patients’ overall survival (p=0.001).
Conclusion: COX-2 overexpression, being possibly a subsequence of apoptosis
activation, due to its positive link with caspase-3, bax-protein and MLH1 and
its inverse correlation to hTERT, is associated with an unfavorable overall
survival in patients with pTa-T1 urothelial carcinomas, suggesting a potential
role of COX-2 in early carcinogenesis. PPARγ expression can identify patients
with a better prognosis who suffer from more dirrerentiated, non-invasive
urothelial carcinomas of low proliferative potential.
Keywords:
COX-2, Apoptosis, Bladder carcinoma, PPAR-γ, Prognosis
