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Title: The role of STAT3 during the human papillomavirus (HPV) life cycle and in HPV-associated cervical cancer
Author: Morgan, Ethan Luc
ISNI:       0000 0004 7654 9462
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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Human papillomaviruses (HPV) activate a number of host factors to control their differentiation-dependent life cycles. The manipulation of these host cell signalling pathways can result in the developement of cancer and HPV is responsible for around 5% of all cancers worldwide. Gaining a better understanding of these virus: host interactions is critical for the development of treatments for HPV infection and associated cancers. The transcription factor signal transducer and activator of transcription (STAT)-3 is important for cell cycle progression and cell survival in response to cytokines and growth factors. STAT3 requires phosphorylation on Ser727, in addition to phosphorylation on Tyr705 to be transcriptionally active. Although STAT3 has been shown to be hyperactive in many cancers, including cervical cancer, there is a paucity of information on the role of STAT3 during the productive HPV life cycle and HPV-associated cancers. Utilising a primary keratinocyte system to study the full HPV life cycle, this study demonstrates that STAT3 is essential for the HPV18 life cycle in both undifferentiated and differentiated keratinocytes. Furthermore, the HPV E6 oncoprotein is identified to be sufficient to induce the dual phosphorylation of STAT3 at Ser727 and Tyr705 by a mechanism requiring Janus kinases and members of the MAPK family. Importantly, silencing of STAT3 protein expression by siRNA or inhibition of STAT3 activation by small molecule inhibitors, or by expression of dominant negative STAT3 phosphorylation site mutants, results in blockade of cell cycle progression. Organotypic raft cultures of HPV18 containing keratinocytes expressing a phosphorylation site STAT3 mutant display a profound reduction in suprabasal hyperplasia, which correlates with a loss of cyclin B1 expression and increased differentiation. Finally, increased STAT3 expression and phosphorylation is observed in HPV positive cervical disease biopsies compared to normal cervical tissue, highlighting a role for STAT3 activation in cervical carcinogenesis. In confirmation of this, STAT3 phosphorylation was demonstrated to be in increased in HPV+ cervical cancer cells when compared to HPV- cervical cancer cells. Detailed mechanistic study identified that this was due to an increase in IL-6 auto/paracrine signalling induce by HPV E6 in an NFkB-dependent manner. Finally, STAT3 was demonstrated to essential for the proliferation, migration and invasion of HPV+ cervical cancer cells. Utilisation of a clinically available inhibitor of JAK2, an upstream kinase for STAT3, also resulted in a similar impairment of proliferation, migration and invasion. In summary, our data provides evidence of a critical role for STAT3 in the HPV18 life cycle and in HPV+ cervical cancer cells. This suggests a possible therapeutic target for both HPV infection and in the treatment HPV+ cervical cancer.
Supervisor: Macdonald, Andrew ; Ranson, Neil Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available