Pontin调控TβRII基因转录及可变剪接活化TGF-β信号通路在胶质瘤侵袭中的机理研究

高度侵袭是导致恶性胶质瘤不易全切、术后易复发的重要原因，由TβRII受体介导的TGF-β信号通路活化是胶质瘤侵袭的研究热点。我们前期发现：(1)ATP酶Pontin在胶质瘤中表达异常升高，且与较差的预后相关；(2)细胞学实验证实Pontin的核定位特点和促侵袭作用；(3)RNA-seq初步分析发现，Pontin敲低后引起TGF-β信号通路抑制、TβRII基因转录及可变剪接失调。据此，我们提出科学假说，Pontin参与TβRII基因转录及可变剪接调控、活化TGF-β信号通路是胶质瘤获得高侵袭性的新机制。本研究拟采用多种分子、细胞、动物实验手段，深入探讨Pontin在胶质瘤侵袭及其他相关恶性生物学行为中的作用，剖析Pontin促进TβRII基因转录及可变剪接的调控机制，以期鉴定胶质瘤中全新的促癌因子Pontin，揭示胶质瘤侵袭新机制，最终为胶质瘤治疗提供可能的新方法和新靶点。

For the malignant glioma, the highly invasive potential principally makes complete tumor resection impossible and easy recurrence after surgery. As the receptor that TGF-β directly binds, TβRII serves as a gatekeeper for TGF-β signaling activation, which is a hotspot of glioma invasion investigation. Our previous results showed that, (1) Pontin, the human ATPase of the AAA+ (ATPases associated with diverse cellular activities) superfamily, was abnormally upregulated in gliomas, and its higher expression was associated with poor prognosis of the glioma patients; (2) Cellular experiments verified the nuclear localization and pro-invasion role of Pontin in glioma cells; (3) Preliminary analysis of the RNA-seq data revealed that, endogenous Pontin knockdown resulted in significant inhibition of the TGF-β signaling pathway and dysregulation of TβRII gene transcription and alternative splicing. According to these results, we propose the hypothesis that, Pontin participates in the regulation of TβRII gene transcription and alternative splicing, thereby activates TGF-β signaling and contributes to glioma invasion. In this project, we aim to adopt molecular, cellular and animal biology techniques, to explore the function of Pontin in invasion and other malignant behaviors of glioma, and to dissect the molecular mechanism of Pontin in regulating TβRII gene transcription and alternative splicing. Taken together, this project will identify the novel onco-protein Pontin in regulating glima invasion, and provides novel strategies and potential therapeutic targets for glioma treatment.