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Title: An investigation of the biological and clinical roles of CD24 in colorectal cancer
Author: Ahmed, Mohamed Abdel Hamid Hasan
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2011
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Background and aims Colorectal cancer (CRC) is a serious health problem with high rate of patient mortality, mostly of tumour metastasis. Identifying new therapeutic target that could hinder metastasis initiation and progression is a high priority research topic. CD24 is a glycosyl phosphatidyl inositol (GPI) anchored membrane protein that has been identified as a marker of differentiation of hematopoietic cells. It has been found to be highly expressed in several tumours and a marker of poor prognosis. More recently, it has been proposed as a marker of cancer stem cells in a number of tumours. However, the biological functions and clinical significance of CD24 have not been fully established yet. Therefore, the aim of the current study is to thoroughly scrutinise the potential biological roles and clinical implications of CD24 in CRC. Material and Methods Following screening of 26 CRC cell lines by RT-PCR, CD24 expression levels were manipulated using a dual approach of knockdown by small interference RNA (siRNA) in cell lines with high CD24 expression and ectopic expression in cell lines with low CD24 expression. Following CD24 manipulation,. functional studies were done in vitro including cell proliferation, colony formation in soft agar, response to external apoptotic stress, cell migration, and invasion. An in vivo metastatic mouse model was also tested. In order to identify potential CD24 downstream targets, (i) a phospho-kinase array was used (and targets validated by Western blotting) and (ii) a gene expression profiling analysis was performed comparing CD24+ and CD24- CRC cells .. Finally, the immunohistochemical expression of CD24 and clinical implication were tested in cases of inflammatory bowel disease, a series of CRC (n = 462) and breast cancer (n=1036). Results CD24 expression significantly enhanced cell migration, invasion and colony formation in soft agar. However, it showed no effect on cell proliferation or resistance to external apoptotic stress. Forced CD24 expression induced an increased metastatic potential in vivo, although this did not quite reach significance (p=O.09). CD24 was shown to possibly function through the activation of AKT at residue Serine-473, and to cooperate with PI3 kinase in inducing full AKT activation. Moreover, CD24 activates focal adhesion kinase, induces cadherin switch and promotes cytoskeletal changes that favour cell migration. CD24 expression was found to be regulated mainly by Wnt signalling, and partly by STAT3. In human tissues, CD24 expression was present in the crypt bases in normal colonic but there was marked up- regulation in inflammatory bowel disease. Up-regulation was also seen in colorectal adenomas and the highest level of expression was in carcinomas. In the studied CRC series, CD24 expression had no prognostic significance and did not show a significant difference between primary CRC and their matched hepatic metastases. Interestingly, CD24 expression in breast cancer showed a trend towards identifying patients with poor prognosis, however, when combined with CD44 immunostaining, cases with CD44-CD24+ phenotype showed the worst prognostic category. Conclusions CD24 is a marker of enhanced cell motility and invasion in CRC and it can endow cells with some features of sternness. These may be important in the tissue healing in inflammatory bowel disease but may also help the development of metastasis. CD24 could provide a potential therapeutic target in early CRC, particularly if combined with therapeutic agents (as for example PI3 kinase inhibitors). CD24 could be used as a prognostic marker in breast cancer but not colorectal cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available