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Title: Elucidating the role of radixin in prostate cancer progression
Author: Clucas, Jarama
ISNI:       0000 0004 8502 8773
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2016
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Introduction: Radixin (RDX) is a member of the ezrin-radixin-moesin (ERM) family of cytoskeletal linkers that have been implicated in cancer progression. Prostate cancer (PC) is the most common cancer of males in the UK. Patients with high grade prostatic intraepithelial neoplasia (HGPIN), the predicted precursor to PC, have shown a significant elevation of RDX expression compared to both normal adjacent tissue and PC samples but its influence in prostate cancer progression remains unclear. Aim: The aim of this thesis was to investigate the role of RDX in the earlier stages of PC progression (such as HGPIN) using 3D cell culture models, microscopy techniques and molecular tools to test the hypothesis that RDX aids the progression of epithelial prostatic cells to a more mesenchymal-like phenotype, in the early stages of PC development. Results: An inducible shRNA system was optimised to successfully knock down RDX expression. The tumourigenic cells WPE-1 NB26, had significantly higher expression of RDX and were chosen to study HGPIN in combination with two improved 3D cell culture models. RDX knock down induced polarisation of WPE-1 NB26-derived spheroids, affecting cell morphology, E-cadherin localisation and laminin 332 expression. Overexpression of a constitutively active RDX mutant in the non-neoplastic cell line, RWPE-1, induced a more mesenchymal-like phenotype. Pharmacological inhibition of atypical protein kinase C (aPKC) reduced the phosphorylation levels of RDX in WPE-1 NB26 cells and localised E-cadherin to the plasma membrane in WPE-1 NB26-derived spheroids. Conclusion: The tools generated and optimised enabled RDX's role in HGPIN to be investigated. RDX was found to maintain the mesenchymal phenotype of acini-like spheroids derived from tumourigenic cells. This phenotype appeared to be aPKC-dependent. Preliminary data indicated the activity of RDX, rather than its expression, mediated a mesenchymal phenotype in non-neoplastic cells. The potential aPKC/RDX/E-cadherin pathway presented in this thesis may provide a therapeutic target to prevent further tumour progression in PC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available