Pituitary tumor-transforming gene regulates multiple downstream angiogenic genes in thyroid cancer.
BACKGROUND
Pituitary tumor-transforming gene (PTTG) is a multifunctional protein involved in several tumorigenic mechanisms, including angiogenesis. PTTG has been shown to promote angiogenesis, a key rate-limiting step in tumor progression, by up-regulation of fibroblast growth factor-2 and vascular endothelial growth factor.


OBJECTIVE
To investigate whether PTTG regulates other angiogenic genes in thyroid cells, we performed angiogenesis-specific cDNA arrays after PTTG transfection. Two of the genes [inhibitor of DNA binding-3 (ID3) and thrombospondin-1 (TSP-1)] which showed differential expression in primary thyroid cells were validated in vitro and in vivo.


RESULTS
TSP-1 showed a 2.5-fold reduction and ID3 showed a 3.5-fold induction in expression in response to PTTG overexpression in vitro. Conversely, suppression of PTTG with small interfering RNA was associated with a 2-fold induction of TSP-1 and a 2.2-fold reduction in ID3 expression. When we examined TSP-1 and ID3 expression in 34 differentiated thyroid cancers, ID3 was significantly increased in tumors compared with normal thyroid tissue. Furthermore, ID3 expression was significantly higher in follicular thyroid tumors than in papillary tumors. Although mean TSP-1 expression was not altered in cancers compared with normal thyroids, we observed a significant independent association between TSP-1 expression and early tumor recurrence, with recurrent tumors demonstrating 4.2-fold lower TSP-1 expression than normal thyroid tissues.


CONCLUSIONS
We have identified ID3 and TSP-1 as two new downstream targets of PTTG in thyroid cancer. We propose that PTTG may promote angiogenesis by regulating the expression of multiple genes with both pro- and antiangiogenic properties and may thus be a key gene in triggering the angiogenic switch in thyroid tumorigenesis.
Kim
D S
DS
Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TH, United Kingdom. daekim72@yahoo.co.uk
Franklyn
J A
JA
Stratford
A L
AL
Boelaert
K
K
Watkinson
J C
JC
Eggo
M C
MC
McCabe
C J
CJ
D045744:Cell Line, Tumor; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D064249:Securin; D019700:Thrombospondin 1 / Q000235:genetics; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000601:surgery; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D064249:Securin; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; C578002:pituitary tumor-transforming protein 1, human; D016222:Fibroblast Growth Factor 2; C075640:ID3 protein, human