胶质瘤发生发展中，STAT3的作用日益受到重视，但其持续活化机制未明。课题组在前期研究中发现Smad6在细胞核中高表达与胶质瘤增殖、干性维持及生存期密切相关，其促癌机制与维持STAT3在胶质瘤中的高活性有关；进一步研究显示Smad6与细胞核内STAT3特异性抑制蛋白PIAS3存在相互作用并在蛋白水平抑制后者的表达，从而拮抗PIAS3对STAT3活性的抑制作用。基于上述研究背景，我们提出本课题的中心假说：胶质瘤细胞核中Smad6通过特定结构域结合PIAS3，并利用PY基序招募的泛素连接酶促进PIAS3的泛素化降解，从而维持STAT3的持续活化促进胶质瘤的发生发展。本项目将通过体内外实验验证该假说，以期解释胶质瘤中Smad6高表达、PIAS3缺失与STAT3异常活化之间的关系及调控机制，为以STAT3为中心的胶质瘤靶向治疗研究提供理论和实验依据。

Accumulating evidence indicates that signal transducer and activator of transcription 3 (STAT3) plays an important role in glioma development. However, the mechanism of sustained STAT3 activation remains unknown. Previously, we found that enhanced nuclear expression of Smad6 is closely related to proliferation and maintenance of stemness of gliomas, as well as patient survival. Sustained elevated STAT3 activity mediated by Smad6 is involved in this cancer-promoting mechanism. Research suggests Smad6 suppressed the expression of STAT3 specific-inhibitor PIAS3 within the nucleus, antagonizing the inhibitory effect of PIAS3 on constitutive STAT3 activation. In the present proposal, we hypothesize that Smad6 binds to PIAS3 via specific domains, recruits ubiquitin ligase via a PY motif and induces ubiquitination and degradation of PIAS3, maintaining activation of STAT3 and promoting glioma development. This project will explore the relationship between elevated Smad6 expression, the lack of PIAS3 and the abnormal activation of STAT3 in glioma, which will provide a new horizon in targeted therapy of glioma.