Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences at Wuhan University, Wuhan 430072, China.
Department of Neurosurgery, The Tenth Affiliated Hospital, Tongji University, Shanghai 200072, China.
J Mol Cell Biol. 2017 Aug 1;9(4):302-314. doi: 10.1093/jmcb/mjx017.
Glioblastoma multiforme (GBM) is a highly invasive brain tumor with limited therapeutic means and poor prognosis. Recent studies indicate that glioma-initiating cells/glioma stem cells (GICs/GSCs) may be responsible for tumor initiation, infiltration, and recurrence. GICs could aberrantly employ molecular machinery balancing self-renewal and differentiation of embryonic neural precursors. Here, we find that paired related homeobox 1 (PRRX1), a homeodomain transcription factor that was previously reported to control skeletal development, is expressed in cortical neural progenitors and is required for their self-renewal and proper differentiation. Further, PRRX1 is overrepresented in glioma samples and labels GICs. Glioma cells and GICs depleted with PRRX1 could not propagate in vitro or form tumors in the xenograft mouse model. The GIC self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor (DRD2). PRRX1 directly binds to the DRD2 promoter and transactivates its expression in GICs. Blockage of the DRD2 signaling hampers GIC self-renewal, whereas its overexpression restores the propagating and tumorigenic potential of PRRX1-depleted GICs. Finally, PRRX1 potentiates GICs via DRD2-mediated extracellular signal-related kinase (ERK) and AKT activation. Thus, our study suggests that therapeutic targeting the PRRX1-DRD2-ERK/AKT axis in GICs is a promising strategy for treating GBMs.
多形性胶质母细胞瘤（GBM）是一种具有侵袭性的脑肿瘤，治疗手段有限，预后较差。最近的研究表明，神经胶质瘤起始细胞/神经胶质瘤干细胞（GICs/GSCs）可能是肿瘤起始、浸润和复发的原因。GICs 可能异常地利用分子机制来平衡胚胎神经前体细胞的自我更新和分化。在这里，我们发现配对相关同源盒 1（PRRX1），一种先前被报道控制骨骼发育的同源域转录因子，在皮质神经祖细胞中表达，并且是其自我更新和适当分化所必需的。此外，PRRX1 在神经胶质瘤样本中过度表达，并标记 GICs。用 PRRX1 耗尽的神经胶质瘤细胞和 GICs 不能在体外增殖，也不能在异种移植小鼠模型中形成肿瘤。PRRX1 调节的 GIC 自我更新功能是由多巴胺 D2 受体（DRD2）介导的。PRRX1 直接结合 DRD2 启动子并在 GIC 中转录激活其表达。阻断 DRD2 信号会阻碍 GIC 的自我更新，而其过表达则恢复了 PRRX1 耗尽的 GIC 的增殖和致瘤潜力。最后，PRRX1 通过 DRD2 介导的细胞外信号调节激酶（ERK）和 AKT 激活来增强 GICs。因此，我们的研究表明，针对 GIC 中 PRRX1-DRD2-ERK/AKT 轴的治疗靶向是治疗 GBM 的一种有前途的策略。
