Activation of sonic hedgehog signaling pathway in olfactory neuroblastoma.
OBJECTIVE
Sonic hedgehog (Shh) signaling pathway is associated with tumor development; however, the role of Shh signaling in the development of olfactory neuroblastoma (ONB) is unknown. This study aimed to investigate the relationship between the regulation of Shh signaling and the pathogenesis of ONB.


METHODS
The expression of Shh signaling components was characterized by immunohistochemistry in human non-tumor olfactory epithelium and ONB specimens, and by RT-PCR and immunoblotting in human ONB cell lines. The impact of the treatment with cyclopamine (a selective inhibitor of the Shh pathway) and/or exogenous Shh on ONB cell proliferation, cycle and apoptosis was examined by MTT, soft agar colony formation and flow cytometry assays, respectively. The influence of Shh signaling on the expression of Shh signaling components and cell cycle-related regulators was determined by immunoblotting and quantitative RT-PCR, respectively.


RESULTS
The expression of Pacthed1, Gli1 and Gli2 was detected in 70, 70, and 65% of human ONB specimens, respectively, and in proportion of ONB cell lines, but not in non-tumor olfactory epithelium. Treatment with cyclopamine inhibited the proliferation and colony formation of ONB cells, induced ONB cell cycle arrest and apoptosis, and down-regulated the expression of Pacthed1, Gli1 and cyclin D1, but up-regulated p21 expression in vitro. These regulatory effects of cyclopamine were partially or completely erased by exogenous Shh.


CONCLUSIONS
These data suggest that the Shh signaling pathway is crucial for the growth of ONB.
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
Wang
Yan-Jun
YJ
Duan
Shu-Jie
SJ
Qiao
Xian
X
Mei
Yuan-Wu
YW
Hu
Bo
B
D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018304:Esthesioneuroblastoma, Olfactory / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000032:analysis / Q000235:genetics; D009296:Nasal Cavity; D009669:Nose Neoplasms / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2