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Title: HAVcR-1 and the prevention of metastatic disease in human prostate cancer
Author: Telford, Emily
ISNI:       0000 0004 7962 1896
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2019
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Introduction: Prostate cancer is a significant burden in the UK, despite continuing research our understanding of disease progression and at present treatment options are still limited. In small studies, Hepatitis A virus cellular receptor (HAVcR-1) has been linked to cancer aetiology and may regulate junctional complexes. Its role in prostate cancer remains unexplored. This study aimed to investigate the expression of HAVcR-1 in prostate cancer samples and explore the cellular and molecular impact of HAVcR-1, with particular focus on junctional complexes, using in vitro models. Methods: Clinical serum samples from prostate cancer patients were tested for HAVcR-1 ectodomain levels through enzyme-linked immunosorbent assay. Clinical prostate cancer samples were tested for the expression of HAVcR-1 through immunohistochemistry. Cell models based on bone metastatic site prostate cancer (PC-3) and normal prostate epithelia (PZ-HPV-7) were employed to evaluate the influence of HAVcR-1 on cellular functions involved in cancer aetiology by use of in vitro functional assays. Cell signalling changes were explored by was or Kinex™ antibody microarray, western blotting analysis, immunofluorescence and polymerase chain reaction (PCR) Results: Levels of HAVcR-1 ectodomain in the serum of patients decreased in the serum of prostate cancer patients compared to healthy controls. Within prostate cancer patients ectodomain levels had no correlation to Gleason score. Histologically, total protein and gene expression of HAVcR-1 were increased in prostate cancer. Manipulation of HAVCR-1 levels within PC-3 cells had no impact on cell growth, invasion, adhesion, transepithelial resistance (TER) and paracellular permeability (PCP). Increased HAVcR-1 expression did however result in decrease PC-3 wound healing. Both increased as well as decreased HAVcR-1 expression increased constrain on current flow beneath cells during initial attachment and spreading as well as decreased barrier function resistance during electrical wound healing. Overexpression of HAVcR-1 in PZ-HPV-7 cells increased invasive potential, adherence to a cell matrix, whilst no changes in migration, TER, PCP and barrier function resistance were observed. At a protein level phosphorylation of β-catenin Y333 was observed in PZ-HPV-7 cells overexpressing HAVcR-1. Further analysis revealed HAVcR-1 overexpression decreased membranous E-cadherin, increased nuclear β-catenin and increased Cyclin D1 protein expression within PZ-HPV-7 cells. Conclusion: This study preliminary shows HAVcR-1 expression and ectodomain release coincides with the presence of prostate cancer thus indicating a potential of HAVcR-1 as a biomarker to aid in diagnostics. Furthermore, it also potentially indicates the involvement ofHAVcR-1 in cancer development, altering cancer associated cellular behaviours. Initial evidence from this study implicates HAVcR-1 in the process of EMT and the dysregulation of junctional complexes. Therefore, highlighting the potential involvement of HAVcR-1 in prostate cancers development and metastatic potential. Differences between cell models may suggest differences in signalling pathways that involve HAVcR-1 and thus further research is required to characterize HAVcR-1 signalling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available