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

EGF-R is Expressed and AP-1 and NF-κ:B Are Activated in Stromal Myofibroblasts Surrounding Colon Adenocarcinomas Paralleling Expression of COX-2 and VEGF

Background:: COX-2 and VEGF are important triggers of colon cancer growth, metastasis and angiogenesis. Cox-2 promoter contains transcriptional regulatory elements for AP-1 and NF-κ:B transcription factors whilst vegf is a known AP-1 downstream target gene. We investigated whether stromal myofibroblasts surrounding colon adenocarcinomas express COX-2 and VEGF and whether activation of AP-1 and NF-κ:B, as well as expression of EGF-R parallel expression of COX-2 and VEGF in these cells. Methods:: Immunohistochemical methodology was performed on archival sections from 40 patients with colon adenocarcinomas. We evaluated c-FOS, p-c-JUN (phosphorylated c-JUN), p-Iκ:B-α (phosphorylated Iκ:B-α), EGF-R, COX-2, NF-κ:B and VEGF expression in stromal myofibroblasts surrounding colon adenocarcinomas. Double immunostaining with a-smooth muscle actin and each antibody was done to verify the expression of these molecules in stromal myofibroblasts. Results:: VEGF, p-Iκ:B-α, NF-κ:B, c-FOS, p-c-JUN, EGF-R and COX-2 were expressed in stromal myofibroblasts surrounding colon adenocarcinomas in the majority of cases. EGF-R, p-Iκ:B-α, NF-κ:B, c-FOS and p-c-JUN correlated positively with COX-2 and VEGF expression. Conclusion:: Stromal myofibroblasts surrounding colon adenocarcinomas are an important source of VEGF and COX-2 production, while AP-1 and NF-κ:B transcription factors are activated and EGF-R is expressed in these cells and associated with COX-2 and VEGF production

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

Expression of ERα, ERβ and Co-Regulator PELP1/MNAR in Colorectal Cancer: Prognostic Significance and Clinicopathologic Correlations

Background: Estrogen receptor β (ERβ) is abundantly expressed in colorectal tissue, but its role in colorectal carcinogenesis remains elusive. ER novel co-regulator, proline-, glutamic acid- and leucine-rich protein 1 (PELP1/MNAR) has been characterized, but its expression in colorectal carcinomas has not been investigated

EGF-R is Expressed and AP-1 and NF-κ:B Are Activated in Stromal Myofibroblasts Surrounding Colon Adenocarcinomas Paralleling Expression of COX-2 and VEGF

Background: COX-2 and VEGF are important triggers of colon cancer growth, metastasis and angiogenesis. Cox-2 promoter contains transcriptional regulatory elements for AP-1 and NF-κ:B transcription factors whilst vegf is a known AP-1 downstream target gene. We investigated whether stromal myofibroblasts surrounding colon adenocarcinomas express COX-2 and VEGF and whether activation of AP-1 and NF-κ:B, as well as expression of EGF-R parallel expression of COX-2 and VEGF in these cells. Methods: Immunohistochemical methodology was performed on archival sections from 40 patients with colon adenocarcinomas. We evaluated c-FOS, p-c-JUN (phosphorylated c-JUN), p-Iκ:B-α (phosphorylated Iκ:B-α), EGF-R, COX-2, NF-κ:B and VEGF expression in stromal myofibroblasts surrounding colon adenocarcinomas. Double immunostaining with a-smooth muscle actin and each antibody was done to verify the expression of these molecules in stromal myofibroblasts. Results: VEGF, p-Iκ:B-α, NF-κ:B, c-FOS, p-c-JUN, EGF-R and COX-2 were expressed in stromal myofibroblasts surrounding colon adenocarcinomas in the majority of cases. EGF-R, p-Iκ:B-α, NF-κ:B, c-FOS and p-c-JUN correlated positively with COX-2 and VEGF expression. Conclusion: Stromal myofibroblasts surrounding colon adenocarcinomas are an important source of VEGF and COX-2 production, while AP-1 and NF-κ:B transcription factors are activated and EGF-R is expressed in these cells and associated with COX-2 and VEGF production