Aurora A is differentially expressed and regulated in chromosomal and microsatellite instable sporadic colorectal cancers.
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.
Lassmann
Silke
S
Institute of Pathology, University Medical Center, Albert-Ludwigs University, Breisacherstrasse 115a, Freiburg, Germany. silke.lassmann@uniklinik-freiburg.de
Danciu
Mihai
M
Müller
Matthias
M
Weis
Roland
R
Makowiec
Frank
F
Schulte-Mönting
Jürgen
J
Hopt
Ulrich T
UT
Werner
Martin
M
D000236:Adenoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D064127:Aurora Kinases; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
D012333:RNA, Messenger; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases