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Nuclear receptor co-repressor actions in bladder cancer

Abedin, Syed Asad (2010)
M.D. thesis, University of Birmingham.

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Abstract

Nuclear receptors (NR) are ligand dependent transcription factors. In the current study, expression of VDR and Farnesoid-X-receptor (FXR) protein is demonstrated along with relative mRNA expression of a range NRs and co-repressors in four bladder cancer cell lines. Nuclear co-repressor 1 (NCoR1) is over-expressed in RT-112 (1.6 fold) and EJ-28 cells (2.6 fold). This correlates with reduced sensitivity to NR ligands in EJ-28 cells. Stable over-expression of NCoR1 in sensitive RT-4 cells (lowest relative NCoR1 expression) led to reduced sensitivity to NR ligands; treatment with lithocholic acid (LCA - FXR and VDR ligand) led to expression of a cohort of genes consistent with a xenobiotic protective response (ABC transporter proteins, metabolizing enzymes and cell cycle arrest proteins) as assessed by microfluidic quantitative real-time reverse transcription polymerase chain reaction. NCoR1 over-expression was targeted with co-treatment with NR ligand and the histone deacetylase inhibitor Suberoylanilide hydroxamic acid (SAHA), resulting in strongly additive anti-proliferative responses to FXR, VDR and PPAR-γ ligands in NCoR1 over-expressing cells; confirmed as a G1/S phase cell cycle arrest in EJ-28. Microarray profiling revealed unique regulation of genes involved in cell proliferation. This study suggests NCoR1 acts as a selective regulator of NR function.

Type of Work:M.D. thesis.
Supervisor(s):Campbell, Moray
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Clinical and Experimental Medicine
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:645
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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