Rapid tumor growth, widespread brain-invasion, and therapeutic resistance critically contribute to glioblastoma (GBM) recurrence and dismal patient outcomes. Although GBM stem cells (GSC) are shown to play key roles in these processes, the molecular pathways governing the GSC phenotype (GBM-stemness) remain poorly defined. Here, we show that epigenetic silencing of miR-146a significantly correlated with worse patient outcome and importantly, miR-146a level was significantly lower in recurrent tumors compared with primary ones. Further, miR-146a overexpression significantly inhibited the proliferation and invasion of GBM patient-derived primary cells and increased their response to temozolomide (TMZ), both in vitro and in vivo. Mechanistically, miR-146a directly silenced POU3F2 and SMARCA5, two transcription factors that mutually regulated each other, significantly compromising GBM-stemness and increasing TMZ response. Collectively, our data show that miR-146a–POU3F2/SMARCA5 pathway plays a critical role in suppressing GBM-stemness and increasing TMZ-response, suggesting that POU3F2 and SMARCA5 may serve as novel therapeutic targets in GBM. Implications: miR-146a predicts favorable prognosis and the miR-146a–POU3F2/SMARCA5 pathway is important for the suppression of stemness in GBM.

中文翻译：

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一种新的 miR-146a-POU3F2/SMARCA5 通路调节胶质母细胞瘤的干性和治疗反应

快速的肿瘤生长、广泛的脑浸润和治疗耐药性是导致胶质母细胞瘤 (GBM) 复发和患者预后不佳的关键因素。尽管 GBM 干细胞 (GSC) 显示在这些过程中发挥关键作用，但控制 GSC 表型（GBM 干细胞）的分子途径仍然不明确。在这里，我们表明 miR-146a 的表观遗传沉默与较差的患者预后显着相关，重要的是，与原发性肿瘤相比，复发性肿瘤中的 miR-146a 水平显着降低。此外，miR-146a 过表达显着抑制了 GBM 患者来源的原代细胞的增殖和侵袭，并增加了它们在体外和体内对替莫唑胺 (TMZ) 的反应。从机制上讲，miR-146a 直接沉默 POU3F2 和 SMARCA5，两个相互调节的转录因子，显着损害 GBM 干性并增加 TMZ 反应。总的来说，我们的数据表明 miR-146a-POU3F2/SMARCA5 通路在抑制 GBM 干性和增加 TMZ 反应方面起着关键作用，表明 POU3F2 和 SMARCA5 可能作为 GBM 的新治疗靶点。意义：miR-146a 可预测良好的预后，并且 miR-146a-POU3F2/SMARCA5 通路对于抑制 GBM 中的干性很重要。