title: Centrosome-, chromosomal-passenger- and cell-cycle-associated mRNAs are differentially regulated in the development of sporadic colorectal cancer.
abstract: Dysregulation of the centrosome complex and chromosomal segregation has been associated with aneuploid cells and aggressive solid tumours, but the relevance of this mechanism to the adenoma-carcinoma sequence of sporadic colorectal cancer (sCRC), especially tumours showing chromosomal instability (CIN), is still unknown. In a series of matching normal epithelial cells (n = 41), dysplastic cells (n = 18), and invasive carcinoma cells (n = 41) from cases with sCRC, mRNA levels of the centrosomal kinase Aurora-A/STK15 and the chromosomal passenger- and cell cycle-associated molecules Incenp, Survivin, Mad-2, and Cyclin-D1 were therefore measured with specific reference to the type of genetic instability. Compared with normal epithelium, significant up-regulation of mRNAs was already present for Aurora-A/STK15 (p = 0.0313) in dysplastic cells and for all investigated markers in invasive carcinoma. Whereas Aurora-A/STK15 mRNA levels were similarly up-regulated in dysplastic and invasive carcinoma cells (p = 0.0797), Survivin (p = 0.0046) and Cyclin-D1 (p = 0.0017) mRNA levels increased from dysplastic to invasive carcinoma cells. In carcinomas, Incenp mRNA correlated with T category (p = 0.0149), and Survivin (p = 0.0382) and Cyclin-D1 (p = 0.0185) were associated with tumour differentiation. Importantly, a significantly higher (p = 0.0419) fold-change of Aurora-A/STK15 mRNA (p = 0.0419), but not Incenp, Survivin, Mad-2 or Cyclin-D1, was observed in sCRC cases with CIN (n = 29) when compared with tumours showing microsatellite instability (MIN, n = 10). The present data are the first to show an early increase of the centrosomal kinase Aurora-A/STK15 in the adenoma-carcinoma sequence of sCRC. The regulation of this kinase differs in CIN- and MIN-type sCRCs and the pattern of changes is different from those of the cell-cycle-associated markers Survivin, Mad-2, and Cyclin-D1. This reinforces the concept of preferential dysregulation of the centrosome complex in CIN-type (aneuploid), compared with MIN-type, sporadic colorectal cancers and may influence the response to and efficiency of novel therapeutics targeting Aurora kinases.
authors.affiliation: Pathologisches Institut, Universitätsklinikum, Freiburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gerlach
authors.forename: Gian
authors.initials: G
authors.lastname: Kayser
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hopt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schulte-Mönting
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.forename: Silke
authors.initials: S
authors.lastname: Lassmann
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000782:Aneuploidy; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002135:Calcium-Binding Proteins / Q000235:genetics; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics; D018385:Centrosome; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins; D064246:Mad2 Proteins; D008297:Male; D018895:Microsatellite Repeats; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D011230:Precancerous Conditions / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D005819:Genetic Markers; C083767:INCENP protein, human; D051034:Inhibitor of Apoptosis Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin; D019938:Cyclin D1; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases