title: Notch1 expression predicts an unfavorable prognosis and serves as a therapeutic target of patients with neuroblastoma.
abstract: OBJECTIVE
  Notch signaling has been implicated to play a critical role in the tumorigenesis of neuroblastoma (NB) and can modulate calreticulin (CRT) expression that strongly correlates with tumor differentiation and favorable prognosis of NB. We thus sought to determine how Notch regulates CRT expression and affects NB tumor behavior.
  
  
  METHODS
  The Notch-dependent regulation of CRT expression in cultured NB cells was analyzed by confocal microscopy and Western blotting. Notch1 protein expression in 85 NB tumors was examined by immunohistochemistry and correlated with the clinicopathologic/biological characters of NB patients. The progression of NB tumors in response to attenuated Notch signaling was examined by using a xenograft mouse model.
  
  
  RESULTS
  We showed that CRT is essential for the neuronal differentiation of NB cells elicited by inhibition of Notch signaling. This effect was mediated by a c-Jun-NH(2)-kinase-dependent pathway. Furthermore, NB tumors with elevated Notch1 protein expression were strongly correlated with advanced tumor stages, MYCN amplification, an undifferentiated histology, as well as a low CRT expression level. Most importantly, the opposing effect between Notch1 and CRT could reciprocally affect the survival of NB patients. The administration of a gamma-secretase inhibitor into a xenograft mouse model of NB significantly suppressed the tumor progression.
  
  
  CONCLUSIONS
  Our findings provide the first evidence that a c-Jun-NH(2)-kinase-CRT-dependent pathway is essential for the neuronal differentiation elicited by Notch signaling blockade and that Notch1 and CRT can synergistically predict the clinical outcomes of NB patients. The present data suggest that Notch signaling could be a therapeutic target for NB.
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taiwan.
authors.forename: Hsiu-Hao
authors.initials: HH
authors.lastname: Chang
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
authors.forename: Ming-Kuan
authors.initials: MK
authors.lastname: Hu
authors.forename: Po-Nien
authors.initials: PN
authors.lastname: Tsao
authors.forename: Hsueh-Fen
authors.initials: HF
authors.lastname: Juan
authors.forename: Min-Chuan
authors.initials: MC
authors.lastname: Huang
authors.forename: Yu-Yin
authors.initials: YY
authors.lastname: Shih
authors.forename: Bo-Jeng
authors.initials: BJ
authors.lastname: Wang
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Christina Ling
authors.initials: CL
authors.lastname: Chang
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.forename: Yeou-Guang
authors.initials: YG
authors.lastname: Tsay
authors.forename: Fon-Jou
authors.initials: FJ
authors.lastname: Hsieh
authors.forename: Kai-Hsin
authors.initials: KH
authors.lastname: Lin
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D011237:Predictive Value of Tests; D011379:Prognosis; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000873:Anthracenes; D037282:Calreticulin; D009842:Oligopeptides; D051881:Receptor, Notch1; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases