A critical role of Sonic Hedgehog signaling in maintaining the tumorigenicity of neuroblastoma cells.
Accumulated evidence suggests a major role for the activation of the Sonic Hedgehog (SHH) signaling pathway in the development of neural crest stem cells that give rise to the sympathetic nervous system. We therefore investigated the involvement of SHH signaling in the pathogenesis of neuroblastoma, a common childhood malignant tumor of the sympathetic nervous system. Human neuroblastoma cell lines and a majority of primary neuroblastoma specimens showed high-level expression of the pathway targets and components, indicating persistent activation of the SHH pathway. All of the neuroblastoma cell lines we examined expressed significant levels of SHH ligand, suggesting an autocrine, ligand-dependent activation of the SHH pathway in neuroblastoma cells. Inhibition of SHH signaling by cyclopamine induced apoptosis and blocked proliferation in all major types of neuroblastoma cells, and abrogated the tumorigenicity of neuroblastoma cells. Moreover, the knockdown of GLI2 in neuroblastoma BE (2)-C and SK-N-DZ cell lines resulted in the inhibition of colony formation. Our study has revealed a molecular mechanism for the persistent activation of the SHH pathway which promotes the development of neuroblastoma, and suggests a new approach for the treatment of this childhood malignant tumor. (Cancer Sci 2009; 100: 1848-1855).
Mao
Ling
L
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xia
Yuan-Peng
YP
Zhou
Yu-Nan
YN
Dai
Ruo-Lian
RL
Yang
Xue
X
Duan
Shu-Jie
SJ
Qiao
Xian
X
Mei
Yuan-Wu
YW
Hu
Bo
B
Cui
Hongjuan
H
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000075746:Zinc Finger Protein Gli2
C530104:CCND1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; C509239:SHH protein, human; D000075746:Zinc Finger Protein Gli2; D019938:Cyclin D1