Coordinated Increased Expression of Cyclooxygenase2 and Nuclear Factor κB Is a Steady Feature of Urinary Bladder Carcinogenesis

Objectives. The inescapable relationship between chronic inflammation and carcinogenesis has long been established. Our objective was to investigate COX-2 and NF-κB immunohistochemical expression in a large series of normal epithelium and bladder carcinomas. Methods. Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from urinary bladder carcinomas of 140 patients (94 males and 46 females with bladder carcinomas). Results. COX-2 expression is increased in the cytoplasm of bladder cells, during loss of cell differentiation (rs = 0.61, P-value < .001) and in muscle invasive carcinomas (P-value < .001). A strong positive association between tumor grade and nuclear expression of NFκB has been established. A positive correlation between COX-2 and nuclear NFκB immunoreactivity was observed. Conclusions. The possible coordinated upregulation of NFκB and COX-2, during bladder carcinogenesis, indicates that agents inhibitors of these two molecules may represent a possible new treatment strategy, by virtue of their role in bladder carcinogenesis

NF-kappa B/PPAR gamma and/or AP-1/PPAR gamma `on/off&apos; switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression

Background and aims: Several studies indicate that peroxisome proliferator-activated receptor gamma (PPAR gamma) represses activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcriptional activity and this negative cross-talk occupies an important role in carcinogenesis. The present study evaluated the differential expression profile of AP-1 constituents (c-FOS and phosphorylated-active pc-JUN), p-I kappa B-alpha (phosphorylated I kappa B-alpha, a signaling intermediate of NF-kappa B pathway), PPAR gamma, cyclic AMP-response element binding-binding protein (CBP, a known AP-1, NF-kappa B, and PPAR gamma transcriptional coactivator), epidermal growth factor receptor (EGF-R), p53, and COX-2 in normal colonic epithelial cells and colon adenocarcinoma cells. Materials and methods: Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from 60 patients with colon adenocarcinomas. A molecular profile was created for each patient and the induction or down-regulation of each pathway from normal to cancer cells was documented. Relationships between transcription factors and downstream molecular targets were evaluated by Spearman’s rho correlation coefficient and validated by nonparametric Kruskal-Wallis test. Results: P-I kappa B-alpha (P &lt; 0.001), CBP (P &lt; 0.001), c-FOS (P=0.047), pc-JUN (P=0.047), and EGF-R (P &lt; 0.001) were up-regulated in colon adenocarcinomas while PPAR gamma (P &lt; 0.001) was concomitantly down-regulated. p-I kappa B-alpha, CBP, pc-JUN, EGF-R, and p53 expression all correlated positively with COX-2 while PPAR gamma expression correlated inversely with COX-2. Interpretation/conclusion: NF-kappa B/PPAR gamma and/or AP-1/PPAR gamma expressional ‘on/off’ switches are common molecular events during colorectal carcinogenesis. Down-regulation of PPAR gamma and induction of the CBP transcriptional coactivator can augment NF-kappa B and AP-1 transcriptional activities leading to up-regulation of COX-2 expression in colon adenocarcinoma cells. p-I kappa B-alpha, pc-JUN, and CBP could potentially provide the basis for future molecular-targeted anticancer therapies