HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS REGISTER		Author Keyword(s) Vol Page [Advanced]

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this link to a friend Similar articles in this journal Similar articles in PubMed Add article to my folders Download to citation manager Request Permissions Google Scholar Articles by Al-Mulla, F Articles by Kolch, W PubMed PubMed Citation Articles by Al-Mulla, F Articles by Kolch, W Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Medline Plus Health Information Colorectal Cancer

Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability

¹ Department of Pathology, Molecular Pathology Unit, Faculty of Medicine, Kuwait University, Kuwait
² Beatson Institute for Cancer Research, Glasgow, UK
³ Department of Surgery, Faculty of Medicine, Kuwait University, Kuwait
⁴ Department of Pharmacology, Faculty of Medicine, Kuwait University, Kuwait
⁵ Section of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, UK

Correspondence to:
F Al-Mulla, Kuwait University, Faculty of Medicine, P.O.Box 24923, Safat, Kuwait, 13110; fahd{at}al-mulla.org

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.