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Title: The expression of EAG and HERG potassium channels in ovarian cancer and their role in cell proliferation
Author: Asher, Viren
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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Background Ovarian cancer is the second most common cancer of the female genital tract in the United Kingdom (UK), accounting for 6% of female deaths due to cancer. This cancer is associated with poor survival and there is a need for new treatments in addition to existing chemotherapy to improve survival. Potassium (K) channels have shown to be promising therapeutic targets in the treatment of various cancers. We sought to determine the expression of EAG and HERG potassium channels in ovarian cancer and establish their role in cell proliferation. Material and Methods The Trent Research and Ethics Committee granted initial approval for the study. Informed consent was obtained from all patients undergoing surgery for ovarian cancer and oopherectomy for benign causes for their participation in the study. The tissues were prospectively collected and analysed anonymously. Immunoflurescence. Immunohistochemistry, Western blotting and Reverse transcriptase Polymerase chain reaction experiments were used to determine the expression of EAG and HERG potassium channels in ovarian cancer and normal ovaries. The effect of the EAG blockers (imipramine and clofilium) and HERG blockers (E-4031 and ergtoxin) on SK~OV-3 ovarian cancer cell line proliferation was assessed using the MTS assay with further investigation of their role in the cell cycle and apoptosis determined by flow cytometry. Results EAG and HERG potassium channels have significant (P<0.001) higher expression in patients with ovarian cancer compared to normal ovarian cells and high expression of EAG channels is significantly associated with poor survival (P=0.016) unlike HERG channel expression where there was no correlation with survival. There was also a significant association of EAG staining with high tumour grade (p=0.014) and presence of residual disease (p=0.011). Proliferation of SK-OV-3 cells was significantly (p<0.001) inhibited after treatment with voltage gated K+ channel blockers. There was significant inhibition of proliferation of SK-OV- 3 ovarian cancer cells by imipramine (p<0.001) and ergtoxin (p<0.05) at 72 hours of culture. Incubation of cells with ergtoxin led to the accumulation of cells in the S and G2IM phase while cells accumulated in S phase after incubation with E-403 1, with no effect on apoptosis.imipramine did not affect the cell cycle but increased the proportion ofSK-OV-3 cells undergoing early apoptosis. Conclusion Both EAG and HERG channels are expressed in ovarian cancer and have a role in cell proliferation. Higher expression of EAG channel is associated with poor prognosis suggesting its role as a poor prognostic marker in patients with ovarian cancer. HERG channels affect the cell cycle while EAG channels are implicated in the inhibition of apoptosis of ovarian cancer cells. EAG channels have the potential to be used as new therapeutic targets in patients with ovarian cancer with use of anti-EAG monoclonal antibody.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available