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Submitted on August 12, 2005
Accepted on December 22, 2005
Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TH, UK
* To whom correspondence should be addressed. E-mail: daekim72{at}yahoo.co.uk.
Context: 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 FGF-2 and VEGF.
Objective: To investigate whether PTTG regulates other angiogenic genes in thyroid cells, we performed angiogenesis-specific cDNA arrays following PTTG transfection. Two of the genes (inhibitor of DNA-binding-3 (ID3) and thrombospondin-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 over-expression in vitro. Conversely, suppression of PTTG with siRNA was associated with a 2-fold induction in 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 raised in tumors compared with normal thyroid tissue. Further, 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.
Conclusion: We have identified ID3 and thrombospondin-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 anti-angiogenic properties, and may thus be a key gene in triggering the angiogenic switch in thyroid tumorigenesis.
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