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Title: Induction of anti-apoptotic factors by cutaneous Human Papillomaviruses
Author: Tomlins, Christine Helen
ISNI:       0000 0004 2700 1812
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2010
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Human Papillomaviruses (HPVs) are small DNA viruses which specifically infect keratinocytes at different body sites. An association between cutaneous Squamous Cell Carcinoma (SCC) formation, UV irradiation and infection with a high-risk subset of cutaneous HPVs has been postulated although the underlying molecular mechanisms by which HPV may play a role in SCC development are not yet fully elucidated. Expression of the viral E6 oncoprotein has been shown to interfere with DNA damage responses and inhibit UV induced apoptosis, suggesting HPV can contribute to early stages in tumourigenesis. Here, expression of E6 from HPV types 5, 8, 10, 18 and 77 was shown to reduce UV- or Fas-induced apoptosis, and the changes in a range of intracellular apoptotic regulators were investigated. Additionally, the subject of cutaneous SCCs, in contrast to HPV-associated anogenital cancers, not harboring HPV DNA in every tumor cell was explored. Results herein show that expression of E6 from skin cancer-associated HPV types 5 and 8 induced the secretion of factors that were able to inhibit UV-induced apoptosis in non-HPV expressing cell lines and primary human keratinocytes. The anti-apoptotic effect of HPV E6 expression was found to be mediated in part by upregulation of Osteoprotegerin (OPG) and Interleukin 6 (IL6). Purified OPG and IL6, when added to cells together, but not individually, reduced apoptosis following UV irradiation. Evidence is shown that OPG and IL6 inhibit the extrinsic and intrinsic apoptotic pathways respectively. Furthermore immunohistochemistry of HPV-typed SCC sections shows that IL6 protein is up-regulated in HPV positive tumors compared to HPV-negative cancers. To further test the effects of HPV5E6 expression, in combination with UV irradiation, on primary human keratinocytes microarray studies were performed. These findings support the hypothesis that a small number of HPV infected cells influence UV induced apoptosis in the skin and contribute to tumourigenesis.
Supervisor: Storey, Alan Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biology ; Medical Sciences ; Biology (medical sciences) ; Oncology ; Viruses ; Human papillomavirus ; ultraviolet ; apoptosis