High copy amplification of the Aurora-A gene is associated with chromosomal instability phenotype in human colorectal cancers

Cancer Biol Ther. 2007 Apr;6(4):525-33. doi: 10.4161/cbt.6.4.3817.

Abstract

Chromosomal instability (CIN) is a common but not universal feature of colorectal cancer (CRC); however, the molecular basis for CIN is controversial and poorly understood. There are many plausible mechanisms proposed for CIN, including disruption of G1/S and G2/M checkpoint regulation, and alterations in the spindle checkpoint genes. However, mutations in individual growth regulatory genes are not commonly observed in CRC. Therefore, a more comprehensive analysis of the genes involved in each cell cycle checkpoint regulatory pathway might be required to evaluate a possible role for involvement in CIN. We investigated the presence of high copy amplification of the cyclin E, Aurora-A, Skp2 genes, mutation of ubiquitin ligase CDC4, and promoter methylation of Mad2L1, as well as the expression of the gene products in a panel of 11 human CRC cell lines as well as 48 human CRC specimens. In the cell lines with CIN, we found amplification of the Aurora-A, cyclin E and Skp2 genes, and a mutation in the CDC4 gene, all of which resulted in altered expression of the cognate proteins. In the human CRC tissues, amplification of Aurora-A was frequent (29%), while alterations were rarely observed in cyclin E, Skp2 or CDC4. Aurora-A amplification was strongly associated with a high fractional allelic loss score (p = 0.0001), but not with microsatellite instability, nor with the promoter methylation phenotype in these tumors. Our data confirm involvement in the CDC4-cyclin E pathway of the development of the CIN phenotype in human CRC, and find that amplification of the Aurora-A is a common target for disruption of this pathway.

MeSH terms

  • Aged
  • Aurora Kinases
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Chromosomal Instability*
  • Colorectal Neoplasms / genetics*
  • Cyclin E / genetics
  • F-Box Proteins / genetics
  • F-Box-WD Repeat-Containing Protein 7
  • Female
  • Gene Amplification*
  • Humans
  • Male
  • Middle Aged
  • Protein-Serine-Threonine Kinases / genetics*
  • S-Phase Kinase-Associated Proteins / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Cell Cycle Proteins
  • Cyclin E
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • S-Phase Kinase-Associated Proteins
  • Ubiquitin-Protein Ligases
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases