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

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 (n71) and dysplastic (n49) colorectal epithelium and invasive carcinomas (n71) 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 (P0.0001; quantitative RT-PCR) and aurora A protein expressing tumour cells (P0.0141; immunohistochemistry) occurred in the adenoma-carcinoma sequence. Within invasive carcinomas, aurora A mRNA levels (P0.0259) and aurora A positive tumour cells (P0.0001) 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 (P0.0043) and a higher tumour cell proliferation (P0.0335). In contrast, only chromosomal instable carcinomas exhibited marked tumour cell aneuploidy (P0.0004, fluorescence in situ hybridization) and significantly higher aurora A gene copy numbers (P0.0206) 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. © 2009 USCAP, Inc. All rights reserved.