期刊
JOURNAL OF MOLECULAR CELL BIOLOGY
卷 9, 期 4, 页码 302-314出版社
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjx017
关键词
paired related homeobox 1; dopamine D2 receptor; glioma-initiating cells; glioblastoma
类别
资金
- National Natural Science Foundation of China [31671418, 31471361]
- National Key Basic Research Program of China [2012CB967002]
- Fundamental Research Funds for the Central Universities [2042016kf1020, 2042017kf0205]
- NIH [HL119478]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL119478] Funding Source: NIH RePORTER
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.
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