Nuclear receptor co-repressor actions in bladder cancer

Abedin, Syed Asad (2010). Nuclear receptor co-repressor actions in bladder cancer. University of Birmingham. M.D.


Download (2MB)


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: Thesis (Higher Doctorates > M.D.)
Award Type: Higher Doctorates > M.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine
Funders: Other
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)


Request a Correction Request a Correction
View Item View Item


Downloads per month over past year