Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability

Br J Cancer. 2005 Sep 19;93(6):719-29. doi: 10.1038/sj.bjc.6602779.

Abstract

Aurora kinases are key regulators of chromosome segregation during mitosis. We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours. We now confirm these observations in a second series of 44 carcinomas and also show that aurora B kinase protein levels are raised in the tumours compared to normal tissue. Elevated levels of expression in tumours are not a consequence of high-level amplification of the AURKB gene. Using a coding sequence polymorphism we show that in most cases (seven out of nine) tumour expression is predominantly driven from one AURKB allele. Given the function of aurora B kinase, we examined whether there was an association between expression levels and genetic instability. We defined two groups of high and low AURKB expression. Using a panel of 10 microsatellite markers, we found that the group showing the higher level of expression had a higher frequency of allelic imbalance (P=0.0012). Analysis of a number of other genes that are strongly and specifically expressed in tumour over normal lung, including SERPINB5, TERT and PRAME, showed marked allelic expression imbalances in the tumour tissue in the context of balanced or only marginally imbalanced relative allelic copy numbers. Our data support a model of early carcinogenesis wherein defects in the process of inactivation of lung stem-cell associated genes during differentiation, contributes to the development of carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allelic Imbalance*
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Catalytic Domain
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Enzymologic*
  • Genes, Tumor Suppressor
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / pathology
  • Microsatellite Repeats
  • Polymorphism, Restriction Fragment Length
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine Proteinase Inhibitors / genetics
  • Serine Proteinase Inhibitors / metabolism
  • Serpins / genetics
  • Serpins / metabolism
  • Telomerase / genetics
  • Telomerase / metabolism
  • Up-Regulation

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • PRAME protein, human
  • SERPIN-B5
  • Serine Proteinase Inhibitors
  • Serpins
  • AURKA protein, human
  • AURKB protein, human
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • TERT protein, human
  • Telomerase