Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells
Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells
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配对相关同源盒 1 反式激活多巴胺 D2 受体以维持神经胶质瘤起始细胞的增殖和致瘤性
DOI：
10.1093/jmcb/mjx017
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发表时间：
2017-08-01
影响因子：
5.5
通讯作者：
Zhou, Yan
中科院分区：
文献类型：
--
作者：
Li, Yamu;Wang, Wen;Zhou, Yan
多形性胶质母细胞瘤（GBM）是一种高度侵袭性脑肿瘤，治疗手段有限，预后不良。最近的研究表明，神经胶质瘤起始细胞/神经胶质瘤干细胞（GIC/GSC）可能与肿瘤的发生、浸润和复发有关。 GIC 可以异常地利用分子机制来平衡胚胎神经前体的自我更新和分化。在这里，我们发现配对相关同源盒 1 (PRRX1) 是一种同源域转录因子，之前被报道可以控制骨骼发育，它在皮质神经祖细胞中表达，是其自我更新和正确分化所必需的。此外，PRRX1 在神经胶质瘤样本和标记 GIC 中的比例过高。 PRRX1耗尽的神经胶质瘤细胞和GIC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 启动子并反式激活其在 GIC 中的表达。阻断 DRD2 信号传导会阻碍 GIC 的自我更新，而其过度表达则可恢复 PRRX1 耗尽的 GIC 的增殖和致瘤潜力。最后，PRRX1 通过 DRD2 介导的细胞外信号相关激酶 (ERK) 和 AKT 激活来增强 GIC。因此，我们的研究表明，针对 GIC 中 PRRX1-DRD2-ERK/AKT 轴的治疗是治疗 GBM 的一种有前途的策略。
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.