Notch1 signaling pathway promotes invasion, self-renewal and growth of glioma initiating cells via modulating chemokine system CXCL12/CXCR4

被引:98
|
作者
Yi, Li [1 ,2 ]
Zhou, Xingchen [3 ]
Li, Tao [1 ,2 ]
Liu, Peidong [1 ,2 ]
Hai, Long [4 ]
Tong, Luqing [1 ,2 ]
Ma, Haiwen [1 ,2 ]
Tao, Zhennan [1 ,2 ]
Xie, Yang [1 ,2 ]
Zhang, Chen [5 ]
Yu, Shengping [1 ,2 ]
Yang, Xuejun [1 ,2 ]
机构
[1] Tianjin Med Univ Gen Hosp, Dept Neurosurg, Tianjin 300052, Peoples R China
[2] Tianjin Neurol Inst, Lab Neurooncol, Tianjin 300052, Peoples R China
[3] Bengbu Med Coll, Dept Neurosurg, Affiliated Hosp 2, Bengbu 233000, Anhui, Peoples R China
[4] Zhengzhou Univ, Henan Canc Hosp, Dept Radiat Oncol, Affiliated Canc Hosp, Zhengzhou 450000, Henan, Peoples R China
[5] Univ Texas MD Anderson Canc Ctr, Neurooncol Dept, Houston, TX 77030 USA
基金
中国国家自然科学基金;
关键词
Glioma initiating cells; Notch1; CXCR4; Invasion; Migration; CANCER STEM-CELLS; INDUCED APOPTOSIS; PRIMARY BRAIN; CXCR4; GLIOBLASTOMA; INHIBITION; SURVIVAL; AKT; CONTRIBUTES; EXPRESSION;
D O I
10.1186/s13046-019-1319-4
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Glioma initiating cells (GICs), also known as glioma stem cells (GSCs), play an important role in the progression and recurrence of glioblastoma multiforme (GBM) due to their potential for self-renewal, multiple differentiation and tumor initiation. In the recent years, Notch1 has been found to be overexpressed in GICs. However, the regulatory mechanism of Notch1 in the self-renewal and invasion ability of GICs remains unclear. This study aims to explore the effect of Notch pathway on self-renewal and invasion of GICs and the underlying mechanisms. Methods Bioinformatic analysis and immunohistochemistry (IHC) were performed to evaluate the expression of Notch1 and Hes1 in GBM samples. Immunofluorescent (IF) staining was performed to observe the distribution of Notch1 and CXCR4 in GBM and GICs. Both pharmacological intervention and RNA interference were employed to investigate the role of Notch1 in GICs self-renewal, invasion and tumor growth in vitro or in vivo. The crosstalk effect of Notch1 and CXCL12/CXCR4 system on GIC self-renewal and invasion was explored by sphere formation assay, limiting dilution assay and Transwell assay. Western blots were used to verify the activation of Notch1/CXCR4/AKT pathway in self-renewal, invasion and tumor growth of GICs. Luciferase reporter assay was used to testify the potential binding site of Notch1 signaling and CXCR4. The orthotopic GICs implantations were established to analyze the role and the mechanism of Notch1 in glioma progression in vivo. Results Notch1 signaling activity was elevated in GBM tissues. Notch1 and CXCR4 were both upregulated in GICs, compared to Notch1 positive glioma cells comprised a large proportion in the CD133+ glioma cell spheres, CXCR4 positive glioma cells which usually expressed Notch1 both and dispersed in the periphery of the sphere, only represent a small subset of CD133+ glioma cell spheres. Furthermore, downregulation of the Notch1 pathway by shRNA and MK0752 significantly inhibited the PI3K/AKT/mTOR signaling pathway via the decreased expression of CXCR4 in GICs, and weakened the self-renewal, invasion and tumor growth ability of GICs. Conclusions These findings suggest that the cross-talk between Notch1 signaling and CXCL12/CXCR4 system could contribute to the self-renewal and invasion of GICs, and this discovery could help drive the design of more effective therapies in Notch1-targeted treatment of GBMs.
引用
收藏
页数:15
相关论文
共 50 条
  • [31] Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity
    Gatti, Monica
    Pattarozzi, Alessandra
    Bajetto, Adriana
    Wuerth, Roberto
    Daga, Antonio
    Fiaschi, Pietro
    Zona, Gianluigi
    Florio, Tullio
    Barbieri, Federica
    TOXICOLOGY, 2013, 314 (2-3) : 209 - 220
  • [32] Signaling of the CXCR4 receptor by the alpha chemokine SDF-1/CXCL12 controls the migration of embryonic neural precursors
    Dubois-Dalcq, M
    Tham, TN
    Vitry, S
    Franceschini, IA
    Lazarini, F
    JOURNAL OF NEUROCHEMISTRY, 2003, 85 : 67 - 67
  • [33] MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis
    Yokoyama, Takashi
    Nakatake, Mayuka
    Kuwata, Takeshi
    Couzinet, Arnaud
    Goitsuka, Ryo
    Tsutsumi, Shuichi
    Aburatani, Hiroyuki
    Valk, Peter J. M.
    Delwel, Ruud
    Nakamura, Takuro
    JOURNAL OF CLINICAL INVESTIGATION, 2016, 126 (05): : 1664 - 1678
  • [34] Adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling
    Goffart, Nicolas
    Kroonen, Jerome
    Di Valentin, Emmanuel
    Dedobbeleer, Matthias
    Denne, Alexandre
    Martinive, Philippe
    Rogister, Bernard
    NEURO-ONCOLOGY, 2015, 17 (01) : 81 - 94
  • [35] ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway
    Wang, Nuozhou
    Li, Ming-yue
    Liu, Yi
    Yu, Jianqing
    Ren, Jianwei
    Zheng, Zhiyuan
    Wang, Shanshan
    Yang, Shucai
    Yang, Sheng-li
    Liu, Li-ping
    Hu, Bao-guang
    Chong, Charing C. N.
    Merchant, Juanita L.
    Lai, Paul B. S.
    Chen, George Gong
    CANCER LETTERS, 2020, 472 : 70 - 80
  • [36] Blockade of CXCL12/CXCR4 signaling inhibits intrahepatic cholangiocarcinoma progression and metastasis via inactivation of canonical Wnt pathway
    Shengqiang Zhao
    Jing Wang
    Chengyong Qin
    Journal of Experimental & Clinical Cancer Research, 33
  • [37] Blockade of CXCL12/CXCR4 signaling inhibits intrahepatic cholangiocarcinoma progression and metastasis via inactivation of canonical Wnt pathway
    Zhao, Shengqiang
    Wang, Jing
    Qin, Chengyong
    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2014, 33
  • [38] A Pilot Study of CXCL12/CXCR4 Chemokine Expression in Sentinel Lymph Node Tracts in Cutaneous Melanoma: An Often Overlooked Signaling Pathway
    Jones, M. S.
    Rivera, M.
    De Guzman, M.
    Puccineli, C. L.
    Williams, S. J.
    Baynosa, J. L.
    St Hill, R.
    Kirgan, D. M.
    ANNALS OF SURGICAL ONCOLOGY, 2014, 21 : S120 - S120
  • [39] The Chemokine Receptors CXCR4/CXCR7 and Their Primary Heterodimeric Ligands CXCL12 and CXCL12/High Mobility Group Box 1 in Pancreatic Cancer Growth and Development Finding Flow
    Shakir, Murtaza
    Tang, Daolin
    Zeh, Herbert J.
    Tang, Siu Wah
    Anderson, Carolyn J.
    Bahary, Nathan
    Lotze, Michael T.
    PANCREAS, 2015, 44 (04) : 528 - 534
  • [40] CXCL12/CXCR4 Axis Promotes the Chemotaxis and Phagocytosis of B Cells through the PI3K-AKT Signaling Pathway in an Early Vertebrate
    Gao, Along
    Lin, Yuhua
    Chai, Yiwen
    Han, Jugan
    Wu, Liting
    Ye, Jianmin
    JOURNAL OF IMMUNOLOGY, 2024, 213 (11):