Title:
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An investigation into the function of the EBV-encoded latent membrane protein (LMP1) in nasopharyngeal carcinoma (NPC)
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Approximately 15-20% of global cancer incidence is causally linked to viral infection.
Although a number of these viruses are implicated in the aetiology of lymphomas or
leukaemias, the vast majority are associated with malignancies of epithelial cells. In epithelial
tissues, several classes of proteins are involved in maintaining tissue architecture, including
those that promote cell-cell adhesion and others which mediate cell-matrix interactions.
Previous studies have shown that the EBV-encoded oncogene, latent membrane protein-l
(LMPl), altered the morphology of SCC12F cells in vitro, downregulated cell-cell adhesion
molecules and promoted cell motility. To understand better the mechanism(s) by which
LMPI induces these effects, transcriptional profiling was performed on SCC12F cells
expressing LMPI under the control of a tetracycline-regulatable promoter. Of the many sets
of genes whose expression was differentially regulated by LMPl, a large number were found
to be characteristically over-expressed in inflammatory and hyperproliferative epidermal
disorders such as psoriasis. These included cytokines and their receptors, growth factors
involved in promoting cutaneous wound healing and cellular proliferation, and signalling
molecules that regulate cell motility. Among the genes whose expression was significantly
induced by LMP1 were activin A, a key orchestrator in the keratinocyte wound response, and
interleukin-l, which is involved in modulating activin A. Findings presented in this thesis
suggest that alterations in the interleukin-l signalling network may be responsible for many of
the changes in host cell gene expression induced in response to LMPI. This helps to define
the mechanism(s) by which this viral oncoprotein may influence cellular pathways regulating
the balance between proliferation and differentiation, cell motility and inflammation, which
are so often deregulated in wounded keratinocytes.
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