ients with Neuroblastoma

ownloade pose: Notch signaling has been implicated to play a critical role in the tumorigenesis of neuroblas(NB) and can modulate calreticulin (CRT) expression that strongly correlates with tumor differenand favorable prognosis of NB. We thus sought to determine how Notch regulates CRT expression ffects NB tumor behavior. erimental Design: The Notch-dependent regulation of CRT expression in cultured NB cells was ed by confocal microscopy and Western blotting. Notch1 protein expression in 85 NB tumors amined by immunohistochemistry and correlated with the clinicopathologic/biological characters patients. The progression of NB tumors in response to attenuated Notch signaling was examined by a xenograft mouse model. ults: We showed that CRT is essential for the neuronal differentiation of NB cells elicited by inhiof Notch signaling. This effect was mediated by a c-Jun-NH2-kinase–dependent pathway. FurtherNB tumors with elevated Notch1 protein expression were strongly correlated with advanced tumor , MYCN amplification, an undifferentiated histology, as well as a low CRT expression level. Most tantly, the opposing effect between Notch1 and CRT could reciprocally affect the survival of NB ts. The administration of a γ-secretase inhibitor into a xenograft mouse model of NB significantly essed the tumor progression. clusions:Our findings provide the first evidence that a c-Jun-NH2-kinase-CRT–dependent pathway ntial for the neuronal differentiation elicited by Notch signaling blockade and that Notch1 and CRT is esse can synergistically predict the clinical outcomes of NB patients. The present data suggest that Notch signaling could be a therapeutic target for NB. Clin Cancer Res; 16(17); 4411–20. ©2010 AACR.