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 responsibl...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.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China （31671418 and 31471361）, the National Key Basic Research Program of China （2012CB967002）, and Fundamental Research Funds for the Central Universities （2042016kf1020 and 2042017kf0205） to Y.Z. and the NIH grant （HL119478） to 6.D.
文摘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.
