Kim D S, Franklyn J A, Stratford A L, Boelaert K, Watkinson J C, Eggo M C, McCabe C J
Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TH, United Kingdom.
J Clin Endocrinol Metab. 2006 Mar;91(3):1119-28. doi: 10.1210/jc.2005-1826. Epub 2006 Jan 4.
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.
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.
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.
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.
垂体肿瘤转化基因（PTTG）是一种多功能蛋白，参与多种致瘤机制，包括血管生成。PTTG已被证明可通过上调成纤维细胞生长因子2和血管内皮生长因子来促进血管生成，这是肿瘤进展中的一个关键限速步骤。
为了研究PTTG是否调节甲状腺细胞中的其他血管生成基因，我们在PTTG转染后进行了血管生成特异性cDNA阵列分析。在原代甲状腺细胞中显示差异表达的两个基因[DNA结合抑制因子3（ID3）和血小板反应蛋白1（TSP-1）]在体外和体内得到了验证。
在体外，响应PTTG过表达，TSP-1表达降低了2.5倍，ID3表达增加了3.5倍。相反，用小干扰RNA抑制PTTG与TSP-1表达增加2倍和ID3表达降低2.2倍有关。当我们检测34例分化型甲状腺癌中的TSP-1和ID3表达时，与正常甲状腺组织相比，肿瘤中的ID3显著增加。此外，滤泡状甲状腺肿瘤中的ID3表达明显高于乳头状肿瘤。虽然与正常甲状腺相比，癌症中的平均TSP-1表达没有改变，但我们观察到TSP-1表达与肿瘤早期复发之间存在显著的独立关联，复发肿瘤的TSP-1表达比正常甲状腺组织低4.2倍。
我们已确定ID3和TSP-1是甲状腺癌中PTTG的两个新下游靶点。我们提出，PTTG可能通过调节具有促血管生成和抗血管生成特性的多个基因的表达来促进血管生成，因此可能是触发甲状腺肿瘤发生中血管生成开关的关键基因。
