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 <
0.001), CBP (P < 0.001), c-FOS (P=0.047), pc-JUN (P=0.047), and EGF-R (P
< 0.001) were up-regulated in colon adenocarcinomas while PPAR gamma (P
< 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