Prrx1通过TGF-β/smads信号环路协同HIF-1α促进胶质瘤干细胞干性及壁龛形成的研究

壁龛微环境的存在可能是单独靶向胶质瘤干细胞(GSC)治疗未能取得显著疗效的关键因素。因此，探索调控GSC及壁龛形成的关键基因并阐明其作用机制对于改善胶质瘤的治疗现状具有重要意义。我们前期研究发现配对相关同源框1（Prrx1）高表达于胶质瘤；敲低Prrx1可以导致GSC的干性标志物表达降低及壁龛生成减少；Prrx1的表达与TGF-β、smads及HIF-1α密切相关，且Prrx1与P-smad2存在共定位现象。据此我们提出假说：Prrx1可作为转录因子和辅助转录因子，分别从上下游激活TGF-β/smads通路，从而形成Prrx1/TGF-β/smads信号环路，并协同HIF-1α促进GSC干性和壁龛形成。本项目拟通过功能和机制研究，结合转录组、蛋白组学和生物信息学等手段验证该假说，以阐明Prrx1调控GSC干性及壁龛形成的作用机制，期望为确立Prrx1作为胶质瘤患者临床治疗靶点提供科学依据。

The existence of the niche microenvironment may be a key factor in the failure of targeted glioma stem cell (GSC) treatment alone to achieve significant results. Therefore, it is of great significance to explore the key genes that regulate the GSC stemness and formation of its niches and clarify their undergoing mechanism for improving the current status of glioma treatment. Our previous research found that paired related homeobox 1 (Prrx1) is highly expressed in gliomas; knockdown of Prrx1 can lead to reduced expression of GSC stem markers and reduced niches; the expression of Prrx1 is closely related to the expression level of TGF-β, smads and HIF-1α. We also found the co-localization of Prrx1 and P-smad2. Based on this, we propose a hypothesis: Prrx1 can play the part of a transcription factor and an auxiliary transcription factor to activate the TGF-β/smads pathway from upstream and downstream respectively, thereby forming the Prrx1/TGF-β/smads signal loop, and cooperate with HIF-1α to promote the GSC stemness and formation of niches. This project intends to verify this hypothesis through functional and mechanism research, combining transcriptome, proteomics, and bioinformatics to elucidate the mechanism of Prrx1 regulating GSC stemness and niches formation. We hope to provide scientific basis for establishing Prrx1 as a clinical treatment target for glioma patients.