title: Aneuploidy facilitates oncogenic transformation via specific genetic alterations, including Twist2 upregulation.
abstract: Aneuploidy, deviation from the normal chromosome number, and other chromosomal aberrations are commonly observed in cancer. Integrin-mediated adhesion and dynamic turnover of adhesion sites are required for successful cytokinesis of normal adherent cells and impaired cell division can lead to the generation of cells with abnormal chromosome contents. We find that repeated cytokinesis failure, due to impaired integrin traffic alone, is sufficient to induce chromosome aberrations resulting in the generation of aneuploid cells with malignant properties. Here, we have compared isogenic aneuploid and euploid cell lines with unravel aneuploidy-induced changes in cellular signaling. Euploid, non-transformed, and aneuploid, transformed, cell lines were investigated using genome-wide gene expression profiling, analysis of deregulated biological pathways and array-comparative genomic hybridization. We find that aneuploidy drives malignancy via inducing marked changes in gene and micro RNA expression profiles and thus imposing specific growth and survival promoting alterations in cellular signaling. Importantly, we identify Twist2 as a key regulator of survival, invasion and anchorage-independent growth in the aneuploid cells. In addition, alterations in lipid biosynthetic pathways and miR-10b upregulation are likely contributors to the malignant phenotype.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, FIN-20520 Turku, Finland.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Högnäs
authors.forename: Saara
authors.initials: S
authors.lastname: Hämälistö
authors.forename: Kirsi
authors.initials: K
authors.lastname: Rilla
authors.forename: Jukka O
authors.initials: JO
authors.lastname: Laine
authors.forename: Vesa
authors.initials: V
authors.lastname: Vilkki
authors.forename: Astrid
authors.initials: A
authors.lastname: Murumägi
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002869:Chromosome Aberrations; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016023:Integrins; D008055:Lipids; C569259:MIRN10 microRNA, mouse; D035683:MicroRNAs; D012097:Repressor Proteins; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse