Arsenic treatment increase Aurora-A overexpression through E2F1 activation in bladder cells

BMC Cancer

Research Article

Ya-Shih Tseng¹  Sheng-Hui Lan²  Yu-Ting Kao²  Shan-Ying Wu²  Hsiao-Sheng Liu³  Chin-Han Wu⁴ 

[1] Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical technology, Tainan, Taiwan;Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan;

关键词: Aurora-A;    Arsenic;    Bladder;    Carcinogenesis;   

DOI  :  10.1186/s12885-017-3253-1

 received in 2016-08-24, accepted in 2017-04-01,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundArsenic is a widely distributed metalloid compound that has biphasic effects on cultured cells. In large doses, arsenic can be toxic enough to trigger cell death. In smaller amounts, non-toxic doses may promote cell proliferation and induces carcinogenesis. Aberration of chromosome is frequently detected in epithelial cells and lymphocytes of individuals from arsenic contaminated areas. Overexpression of Aurora-A, a mitotic kinase, results in chromosomal instability and cell transformation. We have reported that low concentration (≦1 μM) of arsenic treatment increases Aurora-A expression in immortalized bladder urothelial E7 cells. However, how arsenic induces carcinogenesis through Aurora-A activation remaining unclear.MethodsBromodeoxyuridine (BrdU) staining, MTT assay, and flow cytometry assay were conducted to determine cell proliferation. Messenger RNA and protein expression levels of Aurora-A were detected by reverse transcriptional-PCR and Western blotting, respectively.Centrosome of cells was observed by immunofluorescent staining. The transcription factor of Aurora-A was investigated by promoter activity, chromosome immunoprecipitation (ChIP), and small interfering RNA (shRNA) assays. Mouse model was utilized to confirm the relationship between arsenic and Aurora-A.ResultsWe reveal that low dosage of arsenic treatment increased cell proliferation is associated with accumulated cell population at S phase. We also detected increased Aurora-A expression at mRNA and protein levels in immortalized bladder urothelial E7 cells exposed to low doses of arsenic. Arsenic-treated cells displayed increased multiple centrosome which is resulted from overexpressed Aurora-A. Furthermore, the transcription factor, E2F1, is responsible for Aurora-A overexpression after arsenic treatment. We further disclosed that Aurora-A expression and cell proliferation were increased in bladder and uterus tissues of the BALB/c mice after long-term arsenic (1 mg/L) exposure for 2 months.ConclusionWe reveal that low dose of arsenic induced cell proliferation is through Aurora-A overexpression, which is transcriptionally regulated by E2F1 both in vitro and in vivo. Our findings disclose a new possibility that arsenic at low concentration activates Aurora-A to induce carcinogenesis.

【 授权许可】

CC BY   
© The Author(s). 2017