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NF-κB/PPARγ and/or AP-1/PPARγ ‘on/off’ switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

Several studies indicate that peroxisome proliferator-activated receptor gamma (PPARγ) represses activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) 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-IκB-α (phosphorylated IκB-α, a signaling intermediate of NF-κB pathway), PPARγ, cyclic AMP-response element binding-binding protein (CBP, a known AP-1, NF-κB, and PPARγ 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/findings

P-IκB-α (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 PPARγ (P<0.001) was concomitantly down-regulated. p-IκB-α, CBP, pc-JUN, EGF-R, and p53 expression all correlated positively with COX-2 while PPARγ expression correlated inversely with COX-2.

Interpretation/conclusion

NF-κB/PPARγ and/or AP-1/PPARγ expressional ‘on/off’ switches are common molecular events during colorectal carcinogenesis. Down-regulation of PPARγ and induction of the CBP transcriptional coactivator can augment NF-κB and AP-1 transcriptional activities leading to up-regulation of COX-2 expression in colon adenocarcinoma cells. p-IκB-α, pc-JUN, and CBP could potentially provide the basis for future molecular-targeted anticancer therapies.

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Acknowledgements

We thank H. Nikolopoulou, N. Mpeka, and F. Chrysanthopoulos, technicians at the Pathology Department of Aeghion General Hospital, for their help and enthusiastic work. P. A. Konstantinopoulos and G. P. Vandoros contributed equally to this work.

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Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, University of Patras, 26110, Patras, Greece

    Panagiotis A. Konstantinopoulos, Gerasimos P. Vandoros & Athanasios G. Papavassiliou

  2. Department of Anatomy and Histology–Embryology, School of Medicine, University of Patras, Patras, Greece

    Panagiotis A. Konstantinopoulos, Gerasimos P. Vandoros, Georgia Sotiropoulou-Bonikou & Athina Kominea

  3. Department of Pathology, Aeghion General Hospital, Aeghion, Greece

    Gerasimos P. Vandoros & Athina Kominea

  4. Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece

    Athanasios G. Papavassiliou

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  1. Panagiotis A. Konstantinopoulos
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Correspondence to Athanasios G. Papavassiliou.

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Konstantinopoulos, P.A., Vandoros, G.P., Sotiropoulou-Bonikou, G. et al. NF-κB/PPARγ and/or AP-1/PPARγ ‘on/off’ switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression. Int J Colorectal Dis 22, 57–68 (2007). https://doi.org/10.1007/s00384-006-0112-y

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