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The role of MCPyV ST in Merkel cell carcinoma metastasis

Nwogu, Nnenna Onyinyechi Uchechi (2017) The role of MCPyV ST in Merkel cell carcinoma metastasis. PhD thesis, University of Leeds.

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Abstract

Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for metastasis via the dermal lymphatic system. In 2008, Merkel cell polyomavirus (MCPyV) was discovered monoclonally integrated within the host genome of at least 80% of MCC tumours. MCPyV transforms and maintains MCC tumours via the expression of the large and small tumour (LT and ST) antigens. Unlike other polyomaviruses, MCPyV ST is thought to be the major viral transforming factor required for MCC development. Since the discovery of MCPyV, a number of novel functions for ST have been identified which contribute to tumourigenesis, but to date, little is known about potential links between MCPyV T antigen expression and the highly metastatic nature of MCC. Previously, the Whitehouse Laboratory have demonstrated the ability of MCPyV ST to enhance cell motility and migration, suggesting a potential role of MCPyV ST in the highly metastatic nature of MCC. In this thesis, the link between MCPyV ST and MCC metastasis is further explored by focusing on the role of MCPyV ST in promoting early events of initiating cell migration and metastatic spread. Results show that MCPyV ST expression disrupts the integrity of cell-to-cell junctions, thereby enhancing cell dissociation and scatter. Moreover, the functional requirement of cellular sheddases is highlighted in this process, specifically the A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins. These findings therefore suggest MCPyV ST-mediated cell surface accumulation of cellular sheddases play a role in the highly metastatic nature of MCC and may also provide novel therapeutic interventions for disseminated MCC. Furthermore, results explore he potential of MCPyV ST to initiate an Epithelial to mesenchymal transition [EMT]. In addition to disruption of the cell junctions, other hallmarks of EMT are examined including loss of apical to basal polarity, expression of EMT associated Transcription factors and upregulation of Matrix metalloproteinases. Results show that MCPyV ST expression leads to phenotypic changes suggestive of characteristic EMT mechanisms which may further contribute to the metastatic spread associated with MCC.

Item Type: Thesis (PhD)
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute for Molecular and Cellular Biology (Leeds)
Depositing User: Nnenna Onyinyechi Uchechi Nwogu
Date Deposited: 15 Feb 2018 17:09
Last Modified: 15 Feb 2018 17:09
URI: http://etheses.whiterose.ac.uk/id/eprint/19356

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