The role of pttg and pbf in genomic instability and DNA repair in thyroid cancer

[摘要] Thyroid cancer, the most common endocrine malignancy has a rising incidence worldwide. Radiation damage is a known aetiological factor in thyroid tumourigenesis, particularly in children. Pituitary tumor transforming gene (PTTG) and its binding partner (PTTG binding factor; PBF) are overexpressed in thyroid cancers. Critically, PTTG and PBF have been shown to be independent markers of poor prognosis in thyroid cancer. PTTG, a human securin, has multifunctional roles in mitotic control, DNA repair, apoptosis, cell transformation and genomic instability. PBF, which has independent tumourigenic and transforming actions, binds to PTTG, transports it to the nucleus and facilitates its actions within the nucleus. Taken together, the above implicate the functional role of PTTG and PBF in genetic instability. This thesis describes the generation of a transgenic murine model of thyroid cancer which overexpressed both human PTTG and human PBF in the thyroid gland (BI-Trans). The BI-Trans murine model developed goitres from a young age in both genders. Additionally, they develop thyroid adenomas at a later age which had a female preponderance. Unexpectedly, this BI-Trans murine model did not develop cancers. We next measured the index of genetic instability (GI) in the thyroids of our transgenic murine models with fluorescent inter-simple sequence repeat-PCR (FISSR-PCR). This technique was refined to measure GI with small quantities of DNA obtained from murine thyroids. We performed microarray analysis on our murine thyroids with and without ionising radiation to elucidate the mechanism by which PBF and PTTG induced genetic instability.

[发布机构] University:University of Birmingham;Department:Institute of Clinical Sciences

[关键词] R Medicine;RC Internal medicine;RC0254 Neoplasms. Tumors. Oncology (including Cancer)