Molecular mechanisms of human thyroid tumorigenesis

Ball, Elizabeth Louise 2008. Molecular mechanisms of human thyroid tumorigenesis. PhD Thesis, Cardiff University.

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Abstract

Thyroid cancer is the commonest endocrine malignancy. Several of the initiating genetic events in thyroid tumorigenesis have been identified, although the exact molecular mechanisms are unclear. Our thyrocyte model has demonstrated that p16INK4A is up-regulated in RAS-induced colonies which resemble follicular adenomas. Affymetrix microarrays revealed that many interferon-stimulated genes (ISGs) are also up-regulated in these colonies. I hypothesised that p16 expression would be induced in follicular adenomas and lost in follicular cancers, consistent with their escape from growth control, and that ISG expression (HLA-DR, PKR, MxA) would be induced in follicular adenomas. I tested these hypotheses using immunohistochemistry, and correlated p16 expression with cyclin D1 and p21 expression to further investigate growth control. My original research demonstrates that p16 is expressed in adenomas, and surprisingly up-regulated in well-differentiated cancers. Loss of expression was only seen in poorly-differentiated carcinomas. Cyclin D1 expression increased during the transition from a benign to a malignant tumour, whereas p21 protein was expressed at a lower level in both adenomas and carcinomas. Unexpectedly, ISGS were not up-regulated in either the adenomas or carcinomas, but were expressed in some papillary carcinomas. PKR expression was positively correlated with p16 expression. I speculate that there must be two or more growth inhibitory pathways involved in thyroid tumorigenesis, one of which involves p16, and both must be inactivated for progression to a more aggressive phenotype. The cyclin D1 result is explained as a result of growth stimulation during tumorigenesis, whereas the basis and implication of p21 expression is uncertain. Thyroid cancers are unusual because the majority are slow-growing yet potentially fatal despite continued p16 expression. Further work is needed to elucidate the nature of the additional pathways controlling tumour growth, which will improve our understanding of thyroid tumorigenesis, and may potentially lead to the development of novel treatment strategies.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > RB Pathology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ISBN:	9781303183805
Date of First Compliant Deposit:	30 March 2016
Last Modified:	06 Nov 2024 15:17
URI:	https://orca.cardiff.ac.uk/id/eprint/55767

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