Research Papers:

Actin cytoskeleton regulator Arp2/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells

Chen Zhang, Long Hai, Meng Zhu, Shengping Yu, Tao Li, Yu Lin, Bo Liu, Xingchen Zhou, Lei Chen, Pengfei Zhao, Hua Zhou, Yubao Huang, Kai Zhang, Bingcheng Ren and Xuejun Yang _

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Oncotarget. 2017; 8:33353-33364. https://doi.org/10.18632/oncotarget.16495

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Chen Zhang1,2,*, Long Hai1,2,*, Meng Zhu3, Shengping Yu1,2, Tao Li1,2, Yu Lin1,2, Bo Liu1,2, Xingchen Zhou1,2, Lei Chen1,2, Pengfei Zhao1,2, Hua Zhou1,2, Yubao Huang1,2, Kai Zhang1,2, Bingcheng Ren1,2 and Xuejun Yang1,2

1Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

2Tianjin Neurological Institute, Tianjin, 300052, China

3Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China

*These authors have contributed equally to this work

Correspondence to:

Xuejun Yang, email: ydenny@126.com

Keywords: glioma initiating cell, Notch signaling, delta-like1, cytoskeleton, Arp2/3 complex

Received: July 15, 2016     Accepted: March 09, 2017     Published: March 23, 2017


Glioblastoma (GBM) is the most common and lethal primary intracranial tumor. Actin cytoskeleton regulator Arp2/3 complex stimulates glioma cell motility and migration, and thus triggers tumor invasion. However, little is known regarding the role of actin cytoskeleton in maintaining the stem cell phenotype. Here, we showed that Arp2/3 complex improved stem cell phenotype maintenance through sustaining the activated Notch signaling. ShRNA targeting Notch ligand Delta-like 1 (DLL1) decreased CD133 and Nestin expression, and impaired the self-renewal ability of CD133+ U87-MG and U251-MG glioma cells, indicating DLL1/Notch1 signaling promoted stem cell phenotype maintenance. Interestingly, inhibiting Arp2/3 complex also induced the similar effect of shDLL1. Silencing DLL1 in the Arp2/3 inhibited CD133+ cells did not further abrogate the stem cell phenotype, suggesting DLL1 function requires Arp2/3 complex in glioma initiating cells (GICs). However, exogenous soluble DLL1 (sDLL1) instead of endogenous DLL1 rescued the Arp2/3 inhibition-induced stem cell phenotype suppression. The underlying mechanism was that Arp2/3 inhibition impeded DLL1 vesicular transport from cytoplasm to cell membrane, which resulted in DLL1 unable to activate Notch pathway. Furthermore, we illustrated that Arp2/3 inhibition abolished the tumorigenicity of CD133+ U87-MG neurosphere cells in the intracranial model. These findings suggested that cytoskeleton maintained the stem cell phenotype in GBM, which provide novel therapeutic strategy that anti-invasive targeted therapies may help eliminate GICs.

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