Group of Cellular Oncology, Biodonostia Health Research Institute, 20014 San Sebastian, Spain.
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain.
Int J Mol Sci. 2022 Apr 19;23(9):4511. doi: 10.3390/ijms23094511.
Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.
神经胶质瘤干细胞（GSCs）是神经胶质瘤治疗的关键靶点。SOX9 是一种转录因子，在神经发育过程中起着关键作用，尤其是在神经干细胞中。先前的研究表明，SOX9 水平高与胶质瘤患者的生存预后差有关。SOX9 敲低可损害 GSCs 的增殖，证实其有作为神经胶质瘤治疗靶点的潜力。在这项研究中，我们直接在患者来源的神经胶质瘤干细胞中表征了 SOX9 的功能。值得注意的是，SOX9 敲低的 GSCs 的转录组分析显示 STAT3 和 PML 是下游靶点。功能研究表明，SOX9、STAT3 和 PML 形成了一个调控环路，对 GSC 的活性和自我更新至关重要。对神经胶质瘤临床活检的分析证实，在 SOX9 表达水平最高的病例中，SOX9/STAT3/PML 与患者生存预后不良之间存在正相关。重要的是，直接的 STAT3 或 PML 抑制剂降低了 SOX9、STAT3 和 PML 蛋白的表达，显著降低了 GSCs 的致瘤性。总之，我们的研究揭示了 SOX9 在 STAT3 上游作为 GSC 途径调节剂的新作用，并提出了该信号级联的药理学抑制剂。
