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Title: Role of the von Hippel-Lindau tumour suppressor gene in regulating renal epithelial cell characteristics
Author: Harten, Sarah Kay
ISNI:       0000 0001 3541 5298
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene underlies both VHL disease, an inherited multi-cancer syndrome, and the majority of sporadic clear cell renal cell carcinomas (CCRCCs). The best established function of pVHL is regulation of HIF (hypoxia inducible factor). However, how VHL functions as a renal tumour suppressor gene remains to be fully elucidated. There is extensive evidence that changes in cell-cell adhesion and loss of epithelial cytoarchitecture are pivotal in the progression of tumours of epithelial origin, allowing cell-cell dissociation and subsequent invasion. The main objective of this thesis has been to identify whether VHL regulates epithelial cell characteristics, and, if so, whether this is mediated via HIF. The major findings are as follows: First, VHL loss-of-function has striking effects on the expression and localisation of several tight junction (TJ) components (occludin, claudin 1 and ZO-l) in both VHL defective CCRCC cells and sporadic CCRCC tissue (compared to adjacent unaffected kidney). Secondly disruption of TJs was detected in the earliest lesions of VHL inactivation in VHL patient kidneys, suggesting a potential role in tumour initiation. Thirdly re-expression the adherens junction (AJ) protein E-cadherin did not rescue TJ formation, showing that the TJ defect occurs independently of AJ breakage. Fourthly, VHL is required for formation of the primary cilium, a luminal hair-like structure which senses renal tubular flow and which is disturbed in most renal cystic diseases. Finally activation of HIF promotes dedifferentiation of renal epithelial cells. Dedifferentiation may allow cells to tolerate further mutations and undergo full malignant transformation. I have also shown that HDAC inhibitors can reverse this phenotype and therefore may be of use therapeutically. In summary, the work presented in this thesis provides significant insights into understanding how the VHL/HIF pathway contributes to tumour development in both VHL defective renal cancers and hypoxic non-renal tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available