Aurora A is differentially expressed and regulated in chromosomal and microsatellite instable sporadic colorectal cancers

Mod Pathol. 2009 Oct;22(10):1385-97. doi: 10.1038/modpathol.2009.111. Epub 2009 Jul 31.

Abstract

The centrosome-associated kinase aurora A has been shown to be involved in genetic instability and to be (over)expressed in several human carcinomas. This study investigated aurora A gene copy numbers, mRNA and protein expression as well as tumour cell proliferation and aneuploidy in chromosomal and microsatellite instable sporadic colorectal cancers. Case-matched tissues of normal (n=71) and dysplastic (n=49) colorectal epithelium and invasive carcinomas (n=71) were included in this study. PCR-based microsatellite analysis classified 14/71 (20%) of carcinomas as microsatellite instable. A stepwise increase of aurora A mRNA expression (P<0.0001; quantitative RT-PCR) and aurora A protein expressing tumour cells (P=0.0141; immunohistochemistry) occurred in the adenoma-carcinoma sequence. Within invasive carcinomas, aurora A mRNA levels (P=0.0259) and aurora A positive tumour cells (P<0.0001) were closely associated with tumour cell proliferation (Ki-67 specific immunohistochemistry). Compared with chromosomal instable carcinomas, microsatellite instable carcinomas had significantly more aurora A positive tumour cells (P=0.0043) and a higher tumour cell proliferation (P=0.0335). In contrast, only chromosomal instable carcinomas exhibited marked tumour cell aneuploidy (P=0.0004, fluorescence in situ hybridization) and significantly higher aurora A gene copy numbers (P=0.0206) as compared with microsatellite instable carcinomas. This study further supports a role of aurora A in the carcinogenesis of sporadic colorectal cancers. Moreover, it demonstrates that in a minority of predominantly microsatellite instable carcinomas the presence of aurora A positive tumour cells is merely reflecting tumour cell proliferation. In contrast, the large majority of chromosomal instable carcinomas shows additional (de)regulation of aurora A by gene amplification and concomitant tumour cell aneuploidy. Thus, sporadic colorectal cancers exhibit different mechanisms of aurora A regulation and this may impact the efficacy of aurora-targeted therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / enzymology
  • Adenoma / genetics*
  • Adenoma / pathology
  • Aged
  • Aged, 80 and over
  • Aneuploidy
  • Aurora Kinases
  • Carcinoma / enzymology
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Case-Control Studies
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Chromosomal Instability*
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Amplification
  • Gene Dosage
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Polymerase Chain Reaction
  • Protein Serine-Threonine Kinases / analysis
  • Protein Serine-Threonine Kinases / genetics*
  • RNA, Messenger / analysis

Substances

  • RNA, Messenger
  • Aurora Kinases
  • Protein Serine-Threonine Kinases