Hedgehog signaling pathway in neuroblastoma differentiation.
OBJECTIVE
The hedgehog (Hh) signaling pathway is activated in some adult cancers. On the other hand, the Hh signaling pathway plays an important role in the development of the neural crest in embryos. The aim of this study is to show the activation of Hh signaling pathway in neuroblastoma (NB), a pediatric malignancy arising from neural crest cells, and to reveal the meaning of the Hh signaling pathway in NB development.


METHODS
This study analyzed the expression of Sonic hedgehog (Shh), GLI1, and Patched 1 (Ptch1), transactivators of Hh signaling pathway, by immunohistochemistry in 82 NB and 10 ganglioneuroblastoma cases. All 92 cases were evaluated for the status of MYCN amplification.


RESULTS
Of the 92 cases, 67 (73%) were positive for Shh, 62 cases (67%) were positive for GLI1, and 73 cases (79%) were positive for Ptch1. Only 2 (10%) of the 20 cases with MYCN amplification were positive for Shh and GLI1, and 4 cases (20%) were positive for Ptch1 (MYCN amplification vs no MYCN amplification, P ≦ .01). The percentage of GLI1-positive cells in the cases with INSS stage 1 without MYCN amplification was significantly higher than that with INSS stage 4. Of 72 cases without MYCN amplification, 60 were GLI1-positive. Twelve cases were GLI1-negative, and the prognosis of the GLI1-positive cases was significantly better than that of the GLI1-negative cases (P = .015).


CONCLUSIONS
Most of NBs without MYCN amplification were positive for Shh, GLI1, and Ptch1. In the cases without MYCN amplification, the high expression of GLI1 was significantly associated with early clinical stage and a good prognosis of the patients. In contrast to adult cancers, the activation of the Hh signaling pathway in NB may be associated with the differentiation of the NB.
Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ryotas@pedsurg.med.kyushu-u.ac.jp
Ryota
R
Souzaki
Tatsuro
T
Tajiri
Masae
M
Souzaki
Yoshiaki
Y
Kinoshita
Sakura
S
Tanaka
Kenichi
K
Kohashi
Yoshinao
Y
Oda
Mitsuo
M
Katano
Tomoaki
T
Taguchi
D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D002675:Child, Preschool; D005260:Female; D018305:Ganglioneuroblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005784:Gene Amplification; D016259:Genes, myc; D053823:Hedgehog Proteins / Q000032:analysis / Q000502:physiology*; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008297:Male; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1