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Title: Characterisation of apoptotic responses in human keratinocytes expressnig alpha-6 integrin and CD44
Author: Wray, Helen
ISNI:       0000 0004 2693 5074
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2010
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a6 integrin has previously been proposed as a human keratinocyte stem cell markers. CD44-positive cells in epithelial tumours have been identified as potential cancer stem cells (CSCs) and display increased survival following chemotherapy. Keratinocytes expressing CD44 and a high level of a6 integrin (a6 integrinhigh+/CD44+ cells) displayed stem cell-like growth qualities in vitro including the formation of holoclone-like colonies and a high proliferative capacity. Irradiation with ultraviolet-B (UVB) initiated apoptosis in the total keratinocyte population. However, the a6 integrinhigh+/CD44+ cells were significantly resistant to UVB-induced apoptosis. This fraction was also resistant to apoptosis following treatment with the genotoxic agents etoposide, camptothecin and bleomycin. In contrast, the population was highly apoptotic following cisplatin treatment. Addition of the PI3 Kinase inhibitors Wortmannin and LY294002 prior to inducement increased the apoptotic sensitivity of the a6 integrinhigh+/CD44+ cells to UVB. However, pAkt was not directly involved due to the addition of a specific Akt-inhibitor not affecting the resistance of the cells to UVB. Cisplatin can induce p63-mediated apoptosis via c-abl activation. Preincubation with the c-abl kinase inhibitor imatinib significantly reduced the level of cisplatin-induced apoptosis in the a6 integrinhigh+/CD44+ population. Interestingly, the a6 integrinhigh+/CD44+ cells displayed a significantly higher level of TAp63 mRNA compared to the rest of the cell population. The nuclear expression of p63 was reduced, not increased, following cisplatin treatment and imatinib inhibited this loss. This thesis has identified a pattern of apoptotic behaviour not previously characterised in human keratinocytes. a6 integrinhigh+/CD44+ cells display a consistent apoptotic resistance to UVB, etoposide and camptothecin and a 3 sensitivity to cisplatin in vitro. Increased levels of TAp63 and evidence of PI3K and c-abl signalling have provided clues as to the pathways involved in this behaviour.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine