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 - PubMed (original) (raw)

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

S L Smith et al. Br J Cancer. 2005.

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.

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Figures

Figure 1

Representative examples of comparative multiplex RT–PCR analyses of matched normal and tumour tissue (A) and normal human bronchial cells (B) are shown. (C) A Western analysis confirming strong differential expression of aurora B kinase between tumour and matched normal tissue in five tumours. Although approximately equal amounts of protein were loaded, absolute aurora B kinase levels, while clearly higher in tumour in each case, do not appear in all cases to show a close relationship to relative transcript levels.

Figure 2

Progression-free survival of the 39 NSCLC patients with AURKB overexpression (relative expression ⩾2) according to the real-time PCR data presented in Table 1. A threshold of 45.8, representing the mean expression value of these patients, was used to separate patients into two groups, representing excessive (_n_=8) and moderate (_n_=31) AURKB overexpression. The Kaplan–Meier method and log-rank test was used.

Figure 3

AURKB allele-specific expression analyses and corresponding allelic imbalance measurements in matched primary tissues from lung cancer patients. Most tumour samples showed expression strongly biased towards one allele. This is frequently accompanied (six out of seven) by a marginal allelic imbalance in the genomic DNA. The marker track (on all gel images) is a ØX174 _Hae_III digest. Bands representing parental alleles are marked A1/A2.

Figure 4

SERPINB5, PRAME and TERT allele-specific expression analyses and corresponding allelic imbalance measurements in matched primary tissues from lung cancer patients. SERPINB5: Two examples of tumours showing marked AEI in the apparent absence of AI are shown (L61, 194). In the case of L61, weak expression was seen in the matched normal tissue and this shows matching AEI. Patient 230 shows a phase matched AI and AEI in tumour tissue, a balanced normal DNA sample, and an AEI favouring the other allele in the normal cDNA. All samples from patient 227 are balanced. Real time values for over-representation of SERPINB5, relative to APPBP2 in the tumour over matched normal tissue are given below the image. PRAME: Three tumours showing AEI are shown with only L224 having equal co-expression of both alleles. TERT: Telomerase subunit expression was not detected in any normal lung tissue. 5 out of 5 informative samples analysed in duplicate runs showed expression strongly biased towards one parental allele.

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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 - PubMed (original) (raw)