Barod, R.; (2011) Role of the VHL and PTEN tumour suppressors in clear cell renal carcinoma. Doctoral thesis , UCL (University College London).

Abstract

Kidney cancer affects over 7000 people each year in the UK and its incidence is rising. The majority of patients with clear cell renal carcinoma (ccRCC), the commonest form, harbour mutations in the VHL tumour suppressor. Experimental studies have shown that VHL inactivation is an early, important step in the development of ccRCC. The main identified function of VHL is the regulation of hypoxia inducible factor (HIF). HIF has 2 main isoforms (HIF-­1α and HIF-­2α), which act as the master regulator of the cellular response to hypoxia and regulate the transcription of several genes. While loss of VHL function has major effects on cancer related cell behaviour, it is insufficient for ccRCC pathogenesis. Further events are required to promote tumour development. In regard to this, I have investigated 2 main themes in this thesis. First, whether predominant HIF-­2α expression, compared to HIF-­1α, can be identified in tissue from patients with ccRCC, and whether this provides reliable prognostic information. Second, the effect that loss of another tumour suppressor, PTEN, has in VHL -­/-­ ccRCC cells. I identified regions of predominant HIF-­2α expression, with corresponding loss of HIF-­1α expression in a subset of tumours from 3 independent series of ccRCC tissue. I found differential expression of HIF targets in some of these tumours, providing direct in vivo evidence of transcriptional selectivity in ccRCC. These tumours showed a trend towards poorer prognosis, but this did not reach statistical significance. In vitro experiments on the effect of PTEN loss in ccRCC cells showed that PTEN suppresses HIF-­α2, VEGF and other selected HIF targets. Restoration of PTEN in 786-­O cells suppresses cell migration, anchorage independent growth and growth of tumour xenografts in nude mice. Collectively, these results support the hypothesis that after VHL inactivation, further events contribute to ccRCC tumourigenesis. Predominant HIF-­2α expression and PTEN inactivation may be examples of these events. Insights provided from this thesis contribute to the understanding of ccRCC pathogenesis, which ultimately might lead to the development of novel therapeutic strategies to treat this disease.

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