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Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability
  1. F Al-Mulla1,
  2. S Hagan2,
  3. W Al-Ali1,
  4. S P Jacob1,
  5. A I Behbehani3,
  6. M S Bitar4,
  7. A Dallol5,
  8. W Kolch2
  1. 1
    Department of Pathology, Molecular Pathology Unit, Faculty of Medicine, Kuwait University, Kuwait
  2. 2
    Beatson Institute for Cancer Research, Glasgow, UK
  3. 3
    Department of Surgery, Faculty of Medicine, Kuwait University, Kuwait
  4. 4
    Department of Pharmacology, Faculty of Medicine, Kuwait University, Kuwait
  5. 5
    Section of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, UK
  1. F Al-Mulla, Kuwait University, Faculty of Medicine, P.O.Box 24923, Safat, Kuwait, 13110; fahd{at}al-mulla.org

Abstract

Aims: Raf kinase inhibitory protein (RKIP; also known as PEBP, for phosphatidylethanolamine-binding protein) is an endogenous inhibitor of the Raf– MAPK kinase (MEK)–MAP kinase pathway. It has emerged as a significant metastasis suppressor in a variety of human cancers including colorectal cancer (CRC) and was recently shown to regulate the spindle checkpoint in cultured cells. This study aims at correlating RKIP expression with chromosomal instability in colorectal cancer samples and identifies possible mechanisms of RKIP loss.

Methods: Chromosomal instability was assessed using metaphase-based comparative genomic hybridisation (CGH) and loss of heterozygosity (LOH) in 65 cases with microsatellite stable CRC and correlated with RKIP expression. Methyl-specific PCR was used on DNA extracted from 82 cases with CRC to determine CpG methylation status at the RKIP promoter and the results correlated with RKIP protein expression.

Results: We demonstrate for the first time that in microsatellite stable (MSS) CRC, the number of chromosomal losses is inversely proportional to RKIP expression levels. We also show that methylation of the RKIP promoter is a major mechanism by which RKIP expression is silenced in CRC.

Conclusions: RKIP loss by hypermethylation of its promoter could have a significant influence on colorectal cancer aneuploidy, which might explain its association with metastatic progression.

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Footnotes

  • Competing interests: None.

  • Funding: This study was funded by grants from Terry Fox Foundation Canada (TFF 04/05 given to FA-M), Shared Facility Grant GM/0101 from Kuwait University, the Association for International Cancer Research (Grant 02–141), the European Union (FP6 STREP: COSBICS), the Chief Scientist Office of the Scottish Executive Health Department, and Cancer Research UK. The funding organisations did not have any role in the design or conduct of the study; collection, analysis and interpretation of the data; and preparation and review of the manuscript.

  • The procedures followed were in accordance with the ethical standards of implemented at the Universities of Glasgow and Kuwait, and with the Helsinki Declaration of 1975, as revised in 1983.

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