Centrosome-, chromosomal-passenger- and cell-cycle-associated mRNAs are differentially regulated in the development of sporadic colorectal cancer

J Pathol. 2006 Mar;208(4):462-72. doi: 10.1002/path.1914.

Abstract

Dysregulation of the centrosome complex and chromosomal segregation has been associated with aneuploid cells and aggressive solid tumours, but the relevance of this mechanism to the adenoma-carcinoma sequence of sporadic colorectal cancer (sCRC), especially tumours showing chromosomal instability (CIN), is still unknown. In a series of matching normal epithelial cells (n = 41), dysplastic cells (n = 18), and invasive carcinoma cells (n = 41) from cases with sCRC, mRNA levels of the centrosomal kinase Aurora-A/STK15 and the chromosomal passenger- and cell cycle-associated molecules Incenp, Survivin, Mad-2, and Cyclin-D1 were therefore measured with specific reference to the type of genetic instability. Compared with normal epithelium, significant up-regulation of mRNAs was already present for Aurora-A/STK15 (p = 0.0313) in dysplastic cells and for all investigated markers in invasive carcinoma. Whereas Aurora-A/STK15 mRNA levels were similarly up-regulated in dysplastic and invasive carcinoma cells (p = 0.0797), Survivin (p = 0.0046) and Cyclin-D1 (p = 0.0017) mRNA levels increased from dysplastic to invasive carcinoma cells. In carcinomas, Incenp mRNA correlated with T category (p = 0.0149), and Survivin (p = 0.0382) and Cyclin-D1 (p = 0.0185) were associated with tumour differentiation. Importantly, a significantly higher (p = 0.0419) fold-change of Aurora-A/STK15 mRNA (p = 0.0419), but not Incenp, Survivin, Mad-2 or Cyclin-D1, was observed in sCRC cases with CIN (n = 29) when compared with tumours showing microsatellite instability (MIN, n = 10). The present data are the first to show an early increase of the centrosomal kinase Aurora-A/STK15 in the adenoma-carcinoma sequence of sCRC. The regulation of this kinase differs in CIN- and MIN-type sCRCs and the pattern of changes is different from those of the cell-cycle-associated markers Survivin, Mad-2, and Cyclin-D1. This reinforces the concept of preferential dysregulation of the centrosome complex in CIN-type (aneuploid), compared with MIN-type, sporadic colorectal cancers and may influence the response to and efficiency of novel therapeutics targeting Aurora kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / metabolism
  • Adenoma / pathology
  • Adult
  • Aneuploidy
  • Aurora Kinase A
  • Aurora Kinases
  • Calcium-Binding Proteins / genetics
  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Case-Control Studies
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Centrosome
  • Chromosomal Proteins, Non-Histone / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cyclin D1 / genetics
  • Disease Progression
  • Epithelial Cells / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genetic Markers
  • Humans
  • Immunohistochemistry / methods
  • Inhibitor of Apoptosis Proteins
  • Mad2 Proteins
  • Male
  • Microsatellite Repeats
  • Microtubule-Associated Proteins / genetics
  • Neoplasm Proteins / genetics*
  • Precancerous Conditions / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • RNA, Messenger / analysis*
  • Repressor Proteins / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Statistics, Nonparametric
  • Survivin

Substances

  • BIRC5 protein, human
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Genetic Markers
  • INCENP protein, human
  • Inhibitor of Apoptosis Proteins
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • Repressor Proteins
  • Survivin
  • Cyclin D1
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinases
  • Protein Serine-Threonine Kinases