Liu, Jih Way Jacklyn; (2025) Exploring the Role of the EBV-encoded Latent Membrane Protein-1 in the Regulation of Somatostatin Receptor 2, the Wider Impact on Calcium Homeostasis, its Functional Consequences and its role in Nasopharyngeal Carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Nasopharyngeal carcinoma (NPC) is a malignancy of the upper airway tract, which is endemic in East and Southeast Asia and parts of Africa. The predominant subtype in these regions is the undifferentiated, non-keratinising WHO Type III, which is characterised by Epstein-Barr Virus (EBV) infection. NPC is often diagnosed at an advanced stage, which is associated with poor prognosis. The oncoprotein, Latent Membrane Protein 1 (LMP-1), encoded by EBV, is a known driver of malignancy but the precise mechanisms underlying malignant transformation and tumour development remain unresolved. This thesis seeks to improve the present understanding of LMP-1-driven carcinogenesis with the aim of identifying possible molecular targets for future therapeutic development. Using an inducible \textit{in vitro} model, which enables controlled expression of LMP-1, multi-omic and functional characterisation of LMP-1 in the context of malignant transformation is presented. This reveals widespread epigenetic dysregulation of the host genome, including at regions governing the expression of Somatostatin Receptor 2 (SSTR2) and elements of a wider programme of ion dysregulation. \textit{In vitro} studies demonstrate altered calcium dynamics, which is mediated by the large conductance calcium-dependent potassium channel, BK. LMP-1-induced cellular senescence and hypertranscription are also demonstrated. These findings are further supported by single-cell transcriptomics of tumour specimen, which identify a senescent, stem-like population within the malignant bulk. SSTR2, which is widely expressed in NPC and a possible player in the observed calcium activity, is further evaluated using a proof-of-concept digital pathology pipeline, which forms the basis for the development of SSTR2 as a companion diagnostic biomarker. Altogether, these findings highlight the transformative role of LMP-1 in NPC, revealing critical changes to calcium homeostasis, which may be subject to future therapeutic development.

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