Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells

• Published in: Journal of molecular cell biology Vol. 9; no. 4; pp. 302 - 314
• Main Authors: Li, Yamu, Wang, Wen, Wang, Fangyu, Wu, Qiushuang, Li, Wei, Zhong, Xiaoling, Tian, Kuan, Zeng, Tao, Gao, Liang, Liu, Ying, Li, Shu, Jiang, Xiaobing, Du, Guangwei, Zhou, Yan
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.08.2017
• Subjects: Animals; Brain - metabolism; Brain - pathology; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Line, Tumor; Cell Self Renewal; Editor's Choice; Gene Expression Regulation, Neoplastic; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; MAP Kinase Signaling System; Mice, Inbred BALB C; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurogenesis; Original; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Tumor Cells, Cultured; Up-Regulation; 传播; 同源; 多巴胺D2受体; 干细胞; 激活; 胶质瘤; 致瘤性; 配对; paired related homeobox 1; glioblastoma; glioma-initiating cells; dopamine D2 receptor
• ISSN: 1674-2788; 1759-4685; 1759-4685
• DOI: 10.1093/jmcb/mjx017

GUoblastoma multiforme （GBM） is a highly invasive brain tumor with limited therapeutic means and poor prognosis. Recent stud- ies indicate that glioma-initiating ceUs/gUoma stem ceils （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 gUoma samples and labels GlCs. Gtioma celts and GlCs 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 PRRXl-depleted GlCs. Finally, PRRX1 potentiates GICs via DRD2-mediated extracetlutar 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.