Ehrmann J, Strakova N, Vrzalikova K, Hezova R, Kolar Z
Laboratory of Molecular Pathology & Department of Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
Neoplasma. 2008;55(6):482-7.
Proteins of STAT family belongs to the transcription factors. Through their binding to the DNA specific sites and consequent regulation of transcription of various genes, these signaling proteins play an important role in many cell functions. Recent studies demonstrated persistent activation of STATs and loss of their natural inhibitors SOCS and PIAS in various human cancers. There is also evidence that experimental pharmacologic or genetic modulation of their function mignt by a new approach in anticancer treatment. The aim of this study was in vitro assesment and analysis of expression of STATs, SOCS and PIAS in glioblastoma cell lines undergoing treatment by PPARgamma agonists/antagonists because PPARgamma and STATs are tightly regulated by an overlapping set of nuclear regulatory proteins. We further analysed immunohistochemical expression of these proteins in vivo, with its correlation to grading in various brain tumors. The results of in vitro study showed decreased expression of phosphorylated form of STAT3 and increase of its inhibitors SOCS3 and PIAS3 in glioblastoma cell lines after treatment with IC50 of PPARgamma agonist ciglitazone. In vivo study failed to reveal changes in STAT3 and SOCS3 expression in either low and high grade astrocytomas, however we detect lower expression of STAT2 in low grade astrocytomas when comparing with high grade astrocytomas and lower expression of STAT3 in ependymomas when comparing with anaplastic ones. The results showed existing relationship between STAT and PPARgamma signaling in glial tumors and further suppport expected important role of STATs in regulation of growth and differentiation in these tumors.
信号转导和转录激活因子（STAT）家族的蛋白质属于转录因子。通过与DNA特定位点结合并随后调控各种基因的转录，这些信号蛋白在许多细胞功能中发挥重要作用。最近的研究表明，在各种人类癌症中，STAT持续激活，其天然抑制剂细胞因子信号转导抑制因子（SOCS）和蛋白抑制因子（PIAS）缺失。也有证据表明，对其功能进行实验性药理或基因调控可能是抗癌治疗的一种新方法。本研究的目的是在体外评估和分析经过氧化物酶体增殖物激活受体γ（PPARγ）激动剂/拮抗剂处理的胶质母细胞瘤细胞系中STAT、SOCS和PIAS的表达，因为PPARγ和STAT受到一组重叠的核调节蛋白的严格调控。我们进一步分析了这些蛋白在体内的免疫组化表达及其与各种脑肿瘤分级的相关性。体外研究结果显示，用PPARγ激动剂罗格列酮的半数抑制浓度（IC50）处理后，胶质母细胞瘤细胞系中磷酸化形式的STAT3表达降低，其抑制剂SOCS3和PIAS3增加。体内研究未能揭示低级别和高级别星形细胞瘤中STAT3和SOCS3表达的变化，然而，与高级别星形细胞瘤相比，我们检测到低级别星形细胞瘤中STAT2表达较低，与间变性室管膜瘤相比，室管膜瘤中STAT3表达较低。结果表明，胶质肿瘤中STAT与PPARγ信号传导之间存在关联，并进一步支持了STAT在这些肿瘤的生长和分化调控中预期的重要作用。
