PTTG induces genomic instability in thyroid cells

Research output: Contribution to conference (unpublished)Abstract

Abstract

Cancer reflects the progressive accumulation of genetic alterations and subsequent genetic instability of cells. Differentiated thyroid cancers exhibit aneuploidy; cytogenetic studies have demonstrated the importance of genetic instability in thyroid cancer development. Pituitary tumour transforming gene (PTTG), also known as securin, is a mitotic checkpoint protein which inhibits sister chromatid separation during mitosis. PTTG is highly expressed in many cancers and over-expression of PTTG induces aneuploidy in vitro. Inter-(simple sequence repeat)-PCR (ISSR-PCR) allows simple and rapid screening of the human genome for genetic alterations. Using fluorescent-ISSR (FISSR) & ABI377 genotyping platform we investigated the relationship between the degree of genetic instability and PTTG expression in normal and tumour thyroid samples from 26 patients. The genomic instability index (GI-index) was 6.7-72.7% higher in cancers than normal, and in metastatic nodes from 2 patients were 104 & 225% greater than in the corresponding primary cancer. We also found that follicular thyroid tumours exhibited greater genetic instability than papillary tumours (27.6% versus 14.5%, p=0.03). By measuring PTTG mRNA using quantitative-PCR we demonstrated a relationship between PTTG expression and the degree of genetic instability in thyroid cancers (R2=0.80, p=0.007). To further investigate PTTG's role in genetic instability we transfected FTC133 thyroid follicular cells and observed increased genetic instability in cells over-expressing PTTG compared with vector-only controls (n=3, GI-Index VO= 29.7+/-5.2 versus WT-PTTG=63.7+/-6.4, p=0.013). Apoptosis assays demonstrated increased PTTG expression did not induce significant apoptosis. Overall, we describe the first use of FISSR-PCR in human cancers, and demonstrate increased genetic instability in differentiated thyroid cancers and metatstatic nodes compared with normal thyroid tissue. The degree of instability strongly correlated with PTTG-expression in these tissues. Furthermore, in vitro studies demonstrated up-regulation of PTTG in thyroid cells drives genetic instability. We conclude that PTTG may be an important gene in the mutator phenotype development in thyroid cancer.

Details

Original languageEnglish
PagesOC36
Publication statusPublished - 1 Jan 2005
Event24th Joint Meeting of British Endocrine Societies, Harrogate -
Duration: 1 Jan 2005 → …

Conference

Conference24th Joint Meeting of British Endocrine Societies, Harrogate
Period1/01/05 → …