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An investigation into the regulation and expression of the tumour suppressor gene clusterin in oral, cervical and nasopharyngeal cancer

Maloney, Stephanie Louise (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

Clusterin (CLU) is a multifunctional glycoprotein widely expressed as two isoforms. One isoform, sCLU is secreted, cytoplasmic and anti-apoptotic, the other, nCLU, is nuclear and pro-apoptotic. Seven genes, DKK3, TIMP1, CADM1, AKAP12, KLF4, RNASET2 and CLU were identified to be candidate tumour suppressor genes in cervical neoplasia and subsequent validation led to an evaluation of the regulation and expression of CLU at three sites of squamous cancer: the oral cavity, cervix and nasopharynx. Down-regulation of CLU was demonstrated in nasopharyngeal cancer (NPC) and oral cancer and loss of one CLU allele and methylation of the other in the NPC cell line C666-1. This defect has been repaired in this NPC cell line and showed that overexpression of the nuclear isoform of CLU resulted in reduced proliferation and decreased cell viability. Overexpression of both isoforms of CLU in C666-1 cells and their knockdown in HeLa cells regulates NF-kB activity, with a stabilisation of IkB\(\alpha\) following CLU overexpression in C666-1. Although sCLU is now considered a promising therapeutic target because of its anti-apoptotic function, with an antisense oligonucleotide currently undergoing clinical evaluation, results suggest that further consideration needs to be given to the possible tumour suppressor function of nCLU.

Type of Work:Ph.D. thesis.
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Sciences
Keywords:Methylation, NF-kB, loss of heterozygosity, epigenetics
Subjects:QH301 Biology
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
QH426 Genetics
Institution:University of Birmingham
ID Code:612
This unpublished thesis/dissertation is copyright of the author and/or third parties.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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