Consistent gene expression profiles in MexTAg transgenic mouse and wild type mouse asbestos-induced mesothelioma

BMC Cancer

Research Article

Jenette Creaney¹  Richard A. Lake¹  Bruce W. S. Robinson¹  Ian M. Dick¹  Cleo Robinson²  Andrew Holloway³  Dileepa Diyagama³  Michael J. Wise⁴ 

[1] National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, M503, Harry Perkins Institute for Medical Research, QQ Block, QEII Medical Centre, Nedlands, 6009, Perth, Western Australia, Australia;National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, M503, Harry Perkins Institute for Medical Research, QQ Block, QEII Medical Centre, Nedlands, 6009, Perth, Western Australia, Australia;Anatomical Pathology, PathWest Laboratory Medicine, J Block, QEII Medical Centre, Hospital Ave, Nedlands, 6009, Perth, Western Australia, Australia;Present address: Anatomical Pathology, PathWest Laboratory Medicine, J Block, QEII Medical Centre, Hospital Ave, Nedlands, 6009, Perth, Western Australia, Australia;Peter MacCallum Institute for Cancer Research, St. Andrew’s Place, 3002, Melbourne, Victoria, Australia;School of Chemistry and Biochemistry, University of Western Australia, Crawley, 6008, Perth, Western Australia, Australia;

关键词: Mesothelioma;    Mouse models of cancer;    Asbestos;    Gene expression;    Expression microarray;    SV40 large T antigen;   

DOI  :  10.1186/s12885-015-1953-y

 received in 2015-06-21, accepted in 2015-11-23,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe MexTAg transgenic mouse model of mesothelioma replicates many aspects of human mesothelioma, including induction by asbestos, pathogenicity and response to cytotoxic chemotherapy, despite high levels of the SV40 large T Antigen (TAg) in the mesothelial compartment. This model enables analysis of the molecular events associated with asbestos induced mesothelioma and is utilised here to investigate the molecular dynamics of tumours induced in these mice, using gene expression patterns as a read out.MethodsGene expression of MexTAg mesothelioma cell lines bearing a high or low number of copies of the TAg transgene were compared to wild type mouse mesotheliomas and normal mouse mesothelial cells using Affymetrix microarray. These data were then compared to a similar published human microarray study using the same platform.ResultsThe main expression differences between transgenic mouse and wild type mouse mesotheliomas occurred for genes involved in cell cycle regulation and DNA replication, as would be expected from overexpression of the TAg oncogene. Quantitative PCR confirmed that E2F and E2F regulated genes were significantly more upregulated in MexTAg mesotheliomas and MexTAg mesothelial cells compared to wild type mesotheliomas. Like human mesothelioma, both MexTAg and wild type mesotheliomas had more genes underexpressed than overexpressed compared to normal mouse mesothelial cells. Most notably, the cdkn2 locus was deleted in the wild type mouse mesotheliomas, consistent with 80 % human mesotheliomas, however, this region was not deleted in MexTAg mesotheliomas. Regardless of the presence of TAg, all mouse mesotheliomas had a highly concordant set of deregulated genes compared to normal mesothelial cells that overlapped with the deregulated genes between human mesotheliomas and mesothelial cells.ConclusionsThis investigation demonstrates that the MexTAg mesotheliomas are comparable with wild type mouse mesotheliomas in their representation of human mesothelioma at the molecular level, with some key gene expression differences that are attributable to the TAg transgene expression. Of particular note, MexTAg mesothelioma development was not dependent on cdkn2 deletion.

【 授权许可】

CC BY   
© Robinson et al. 2015