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Title: The role of Microcephalin in epithelial ovarian cancer
Author: Alsiary, Rawiah Abdullah S.
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2013
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Ovarian cancers are frequently diagnosed at advance stage with a high mortality rate. Investigating prospective biomarkers are crucial to understand the molecular defects behind ovarian cancer. WPM encodes the protein Microcephalin involved in the DNA damage response and cell cycle pathways. MCPH1 is also known, as BRIT1 (BRCT-repeat inhibitor of hTERT expression). MCPH1 is a potential tumour suppressor gene since defects in these pathways may cause carcinogenesis. Microcephalin expression was identified by immunofluorescence in primary EOC cultures derived from epithelial ovarian cancer (EOC) patients. Patients with weak nuclear Microcephalin presented with high grade tumours. Cytoplasmic Microcephalin increased with tumour grade (p = 0.04). Patients with weak nuclear Microcephalin had a reduced survival rate (p = 0.081). MCPH1 might be a tumour suppressor gene and aberrant localization of Microcephalin involve in tumour development. Microcephalin was evaluated in EOC tissue by immunohistochemistry. Low Microcephalin expression was identified in high grade (p < 0.0001) and advance stage EOC (p = 0.0438). Therefore, Microcephalin is a potential prognostic biomarker. However, immunofluorescence and florescence activated cell sorting indicated that there was no correlation between Microcephalin expression and mitotic defects or aneuploidy. The association between MCPH1 and telomerase activity and alternative splicing of the catalytic subunit (hTERT) was examined. Four different hTERT splice variants were assayed by qRT-PCR. A negative correlation was identified between MCPH1 and the WT hTERT (p = 0.03). Strong positive associations with the hTERT sand a/13-deletion hTERT were reported (p = 0.03, p = 0.04 respectively). This supports the regulatory effect of MCPH1 on telomerase activity. The association between MCPH1 and a-deletion hTERT was confirmed in ovarian cancer cell lines using a hTERT a-deletion plasmid construct. To further elucidate the function of MCPH1, gene expression profiling was performed. Thirty-two pathways were affected by MCPH1 siRNA knockdown including mRNA processing. We proposed that MCPH1 might have a novel role in the mRNA processing pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available