Arch Hellen Med, 24(2), March-April 2007, 155-159
Contribution of AP-1/PPARă/NF-ęB cross talk to COX-2 overexpression in colon adenocarcinomas
P.A. KONSTANTINOPOULOS,1* G.P. VANDOROS,2,3* M. GKERMPESI,2 G. SOTIROPOULOU-BONIKOU,3 A.G. PAPAVASSILIOU1,4
*P.A. Konstantinopoulos and G.P. Vandoros contributed equally to this work
OBJECTIVE The exact role of activator protein-1 (AP-1), nuclear factor-ęB (NF-ęB) and peroxisome proliferatoractivated receptor ă (PPARă) in the development of colon cancer remains to be elucidated. Cox-2 promoter contains transcriptional regulatory elements for various transcription factors including AP-1 and NFęB. This study evaluated the expression of c-FOS, phosphorylated-active c-JUN (pc-JUN), phosphorylated IęBá, a signaling intermediate of the NF-ęB pathway (pIęB-á), CBP (a known AP-1, NF-ęB and PPARă transcriptional coactivator), epidermal growth factor receptor (EGFR), p53, PPARă and COX-2 in normal colonic epithelial cells and colon adenocarcinoma cells.
METHOD Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from 60 patients with colon adenocarcinoma. A "molecular profile" was created for each patient for both normal colonic epithelial cells and colon adenocarcinoma cells. Relationships between transcription factors and downstream molecular targets were evaluated by Spearman's rho correlation coefficient and all results were further validated by nonparametric Kruskall-Wallis test.
RESULTS pIęB-á was overexpressed in 81.7% of the adenocarcinomas as compared to adjacent normal colon and correlated positively with COX-2 (Spearman's rho=0.513, P<0.001). PPARă was down-regulated in 77.3% of the adenocarcinomas and correlated inversely with COX-2 (Spearman's rho=-0.412, P=0.001) and pIęB-á (Spearman's rho=-0.444, P<0.001). CBP was induced in 50% of the cases and its expression correlated positively with COX-2 (Spearman's rho=0.461, P<0.001). Induction of EGFR and pc-JUN was detected in 41.7% and 43.3% of the cases, respectively, and their expression correlated positively with COX-2 (Spearman's rho=0.444, P<0.001 and Spearman's rho=0.431, P<0.001, respectively). Moreover, p53 expression correlated positively with COX-2 (Spearman's rho=0.435, P=0.004).
CONCLUSIONS The results of this study indicate that activation of the EGFR-MAPK-AP-1 and NF-ęB pathways and down-regulation of PPARă expression are important events in colon carcinogenesis. The correlations between AP-1, NF-ęB, PPARă and COX-2 lead to the proposal of a dynamic molecular model to explain COX-2 induction in colon adenocarcinomas. The clinical implications of this model in chemoprophylaxis and treatment of colorectal cancer are discussed.
Key words: Colon cancer, Cross talk, Cyclooxygenase-2, Molecular-targeted anticancer therapies, Transcription factors.