title: Centrosome abnormalities are frequently observed in non-small-cell lung cancer and are associated with aneuploidy and cyclin E overexpression.
abstract: Centrosome abnormalities are observed in human cancers and have been associated with aneuploidy, a driving force in tumour progression. However, the exact pathways that tend to cause centrosome abnormalities have not been fully elucidated in human tumours. Using a series of 68 non-small-cell lung carcinomas and an array of in vitro experiments, the relationship between centrosome abnormalities, aneuploidy, and the status of key G1 to S-phase transition cell-cycle molecules, involved in the regulation of centrosome duplication, was investigated. Centrosome amplification and structural abnormalities were common (53%), were strongly related to aneuploidy, and, surprisingly, were even seen in adjacent hyperplastic regions, suggesting the possibility that these are early lesions in lung carcinogenesis. Cyclin E and E2F1 overexpression, but not p53 mutation, was observed to correlate with centrosome abnormalities in vivo (p = 0.029 and p = 0.015, respectively). This was further strengthened by the observation that cyclin E was specifically present in the nucleus and/or cytoplasm of the cells that contained centrosome aberrations. The cytoplasmic cyclin E signal may be attributed, in part, to the presence of truncated low-molecular-weight isoforms of cyclin E. In order to isolate the effect of cyclin E on the appearance of centrosome abnormalities, a U2OS tetracycline-repressible cyclin E cell line that has a normal centrosome profile by default was used. With this system, it was confirmed in vitro that persistent cyclin E overexpression is sufficient to cause the appearance of centrosome abnormalities.
authors.affiliation: Molecular Carcinogenesis Group, Laboratory of Histology-Embryology, Medical School, University of Athens, Greece.
authors.forename: M K
authors.initials: MK
authors.lastname: Koutsami
authors.forename: P K
authors.initials: PK
authors.lastname: Tsantoulis
authors.forename: M
authors.initials: M
authors.lastname: Kouloukoussa
authors.forename: K
authors.initials: K
authors.lastname: Apostolopoulou
authors.forename: I S
authors.initials: IS
authors.lastname: Pateras
authors.forename: Z
authors.initials: Z
authors.lastname: Spartinou
authors.forename: A
authors.initials: A
authors.lastname: Drougou
authors.forename: K
authors.initials: K
authors.lastname: Evangelou
authors.forename: C
authors.initials: C
authors.lastname: Kittas
authors.forename: J
authors.initials: J
authors.lastname: Bartkova
authors.forename: J
authors.initials: J
authors.lastname: Bartek
authors.forename: V G
authors.initials: VG
authors.lastname: Gorgoulis
mesh_terms: D000368:Aged; D000782:Aneuploidy; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D018385:Centrosome / Q000648:ultrastructure*; D016009:Chi-Square Distribution; D019927:Cyclin E / Q000235:genetics*; D050687:E2F1 Transcription Factor / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D018709:Statistics, Nonparametric
chemical_list: D019927:Cyclin E; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human