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Tumor Biology

, Volume 31, Issue 5, pp 503–511 | Cite as

Hypermethylation of RARβ2 correlates with high COX-2 expression and poor prognosis in patients with colorectal carcinoma

  • Imen Miladi-Abdennadher
  • Rania Abdelmaksoud-Damak
  • Lobna Ayadi
  • Abdelmajid Khabir
  • Foued Frikha
  • Lamia Kallel
  • Ali Amouri
  • Mounir Frikha
  • Tahia Sellami-Boudawara
  • Ali Gargouri
  • Raja Mokdad-Gargouri
Research Article

Abstract

Silencing of gene expression by aberrant methylation at the CpG islands is common in human tumors, including colorectal cancer. This epigenetic alteration affects promoter of genes having crucial cellular functions such as tumor suppressor, DNA repair, apoptosis, cell adhesion, etc. We investigated the methylation status in the promoter regions of the RARβ2, RASSF1A, DAPKinase, and CDH1 genes in 73 colorectal carcinoma and 43 paired normal tissues of Tunisian patients using methylation-specific PCR assays. The association between methylation status and the clinicopathological features was evaluated. To determine whether aberrant methylation affects gene expression, we performed immunohistochemistry analysis for E-cadherin and COX-2, a target gene of RARβ2. The methylation frequencies vary from 80.8% for RARβ2 to 35.6% for RASSF1A while in non-tumor-paired samples; the frequencies of methylation are significantly lower for all the fourth genes tested. The methylation status did not correlate with any of the clinical features considered; however, aberrant methylation of RARβ2 was associated with a shortened overall patients’ survival (p logrank = 0.026); nevertheless, it needs to be confirmed on larger sample size. Moreover, a significant inverse association was observed between methylation status of RARβ2 and COX-2 protein expression in tumor specimen (p = 0.014). On the other hand, we found that loss of E-cadherin expression was significantly associated with aberrant methylation of the CDH1 promoter (p = 0.005). Our findings showed that RARβ2 was frequently methylated in colorectal cancer and correlated with a worse prognosis and high expression of COX-2 suggesting a link between these two proteins in colorectal carcinogenesis. We also showed that epigenetic alteration of CDH1 is a major mechanism of the loss of E-cadherin protein expression in primary colorectal tumors.

Keywords

Colorectal cancer Promoter methylation Prognosis Tumor suppressor genes 

Notes

Acknowledgments

This work was supported by a grant from the “Ministère de l′Enseignement Supérieur et de la Recherche Scientifique Tunisien.” We thank the technicians at CHU Habib Bourguiba at Sfax Tunisia for assistance.

Competing interests

The authors declare that they have no competing interests.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2010

Authors and Affiliations

  • Imen Miladi-Abdennadher
    • 1
  • Rania Abdelmaksoud-Damak
    • 1
  • Lobna Ayadi
    • 2
  • Abdelmajid Khabir
    • 2
  • Foued Frikha
    • 2
  • Lamia Kallel
    • 2
  • Ali Amouri
    • 2
  • Mounir Frikha
    • 2
  • Tahia Sellami-Boudawara
    • 2
  • Ali Gargouri
    • 1
  • Raja Mokdad-Gargouri
    • 1
  1. 1.Centre de Biotechnologie de SfaxSfaxTunisia
  2. 2.Centre HospitaloUniversitaire Habib BourguibaSfaxTunisia

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