title: Pituitary tumour transforming gene (PTTG) induces genetic instability in thyroid cells.
abstract: Cancer reflects the progressive accumulation of genetic alterations and subsequent genetic instability of cells. Cytogenetic studies have demonstrated the importance of aneuploidy in differentiated thyroid cancer development. The 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 overexpression of PTTG induces aneuploidy in vitro. Using fluorescent intersimple sequence repeat PCR (FISSR-PCR), we investigated the relationship between PTTG expression and the degree of genetic instability in normal and tumorous thyroid samples. The genomic instability index (GI index) was 6.7-72.7% higher in cancers than normal thyroid tissues. Follicular thyroid tumours exhibited greater genetic instability than papillary tumours (27.6% (n=9) versus 14.5% (n=10), P=0.03). We also demonstrated a strong 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 overexpressing PTTG compared with vector-only-transfected controls (n=3, GI Index VO=29.7+/-5.2 versus PTTG=63.7+/-6.4, P=0.013). Further, we observed a dose response in genetic instability and PTTG expression (GI Index low dose (0.5 microg DNA/ six-well plate) PTTG=15.3%+/-1.7 versus high dose (3 microg DNA) PTTG=50.8%+/-3.3, P=0.006). Overall, we describe the first use of FISSR-PCR in human cancers, and demonstrate that PTTG expression correlates with genetic instability in vivo, and induces genetic instability in vitro. We conclude that PTTG may be an important gene in the mutator phenotype development in thyroid cancer.
authors.affiliation: Division of Medical Sciences, 2nd Floor IBR, University of Birmingham, Edgbaston, Birmingham B12 5TT, UK. daekim72@yahoo.co.uk
authors.forename: Dae
authors.initials: D
authors.lastname: Kim
authors.forename: Helen
authors.initials: H
authors.lastname: Pemberton
authors.forename: Anna L
authors.initials: AL
authors.lastname: Stratford
authors.forename: Kristien
authors.initials: K
authors.lastname: Buelaert
authors.forename: John C
authors.initials: JC
authors.lastname: Watkinson
authors.forename: Victor
authors.initials: V
authors.lastname: Lopes
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: Chris J
authors.initials: CJ
authors.lastname: McCabe
mesh_terms: D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D042822:Genomic Instability; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D064249:Securin; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; D012333:RNA, Messenger; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases