Journal
NEOPLASIA
Volume 21, Issue 7, Pages 721-729Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2019.04.009
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Funding
- Intramural Research Program, National Cancer Institute/NIH
- Deutsche Krebshilfe, GE through the Deutsche Forschungsgemeinschaft
- Instituto de Salud Carlos III
- CIBEREHD program
- CERCA Program (Generalitat de Catalunya)
- Agencia de Gestio d'Ajuts Universitaris i de Recerca, Generalitat de Catalunya [2017 SGR 1035]
- Mildred Scheel postdoctoral scholarship of the German Cancer Aid (Deutsche Krebshilfe)
- European Regional Development Fund (ERDF) [CP13/00160, CPII18/00026, PI14/00783]
- NATIONAL CANCER INSTITUTE [ZIHBC011703] Funding Source: NIH RePORTER
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Chromosomal aneuploidy is a defining feature of epithelial cancers. The pattern of aneuploidies is cancer-type specific. For instance, the gain of chromosome 13 occurs almost exclusively in colorectal cancer. We used microcell-mediated chromosome transfer to generate gains of chromosome 13 in the diploid human colorectal cancer cell line DLD-1. Extra copies of chromosome 13 resulted in a significant and reproducible up-regulation of transcript levels of genes on chromosome 13 (P = .0004, FDR = 0.01) and a genome-wide transcriptional deregulation in all 8 independent clones generated. Genes contained in two clusters were particularly affected: the first cluster on cytoband 13q13 contained 7 highly up-regulated genes (NBEA, MAB21L1, DCLK1, SOHLH2, CCDC169, SPG20 and CCNA1, P = .0003) in all clones. A second cluster was located on 13q32.1 and contained five upregulated genes (ABCC4, CLDN10, DZIP1, DNAJC3 and UGGT2, P = .003). One gene, RASL11A, localized on chromosome band 13q12.2, escaped the copy number-induced overexpression and was reproducibly and significantly down-regulated on the mRNA and protein level (P = .0001, FDR = 0.002). RASL11A expression levels were also lower in primary colorectal tumors as compared to matched normal mucosa (P = .0001, FDR = 0.0001. Overexpression of RASL11A increases cell proliferation and anchorage independent growth while decreasing cell migration in +13 clones. In summary, we observed a strict correlation of genomic copy number and resident gene expression levels, and aneuploidy dependent consistent genome-wide transcriptional deregulation.
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