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Title: Novel pathways promoting thyroid tumourigenesis and growth
Author: Lewy, Gregory Douglas
ISNI:       0000 0004 2730 6034
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2012
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Thyroid cancers are the most common endocrine malignancies and their incidence continues to rise. Over-expression of the human pituitary tumor transforming gene (hPTTG) in thyroid carcinomas is a prognostic indicator of tumour recurrence. hPTTG is multifunctional with roles in mitotic control, DNA repair, genetic instability, cell transformation and apoptosis. Importantly, hPTTG transactivates expression of growth factors implicated in proliferation and angiogenesis, and represses the sodium iodide symporter (NIS), which is essential to radioiodine treatments in thyroid cancer. hPTTG interacts with a binding factor (PBF) which is an independent transforming gene and also represses iodine uptake. Work described in this thesis provides evidence for the existence of thyroidal autocrine regulatory pathways involving hPTTG and growth factors in vitro. We directly investigated the role of hPTTG in thyroid tumourigenesis through the generation and characterisation of a murine transgenic model with thyroid-targeted hPTTG over-expression (hPTTG-Tg mice). Unexpectedly, hPTTG over-expression was not sufficient for thyroid tumourigenesis. Investigations performed in hPTTG-Tg and Pttg-/- knockout mice indicated a particularly important relationship between hPTTG and the epidermal growth factor (EGF) in vivo. hPTTG and PBF were confirmed as repressors of NIS in vivo following studies in hPTTG-Tg and PBF-Tg mice respectively. The studies described in this thesis highlight the therapeutic potential of targeting hPTTG and PBF in thyroid cancer. To this effect, specific tyrosine kinase inhibitors prevented autocrine induction of hPTTG by growth factors, and siRNA depletion of PBF restored NIS function to normal levels in hPBF-Tg thyrocytes. Based on these data, hPTTG appears to play a dual role in endocrine tumourigenesis, being involved in both tumour initiation and subsequent progression towards more aggressive phenotypes.
Supervisor: Not available Sponsor: MRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)