Notch1 expression predicts an unfavorable prognosis and serves as a therapeutic target of patients with neuroblastoma
Journal
Clinical Cancer Research
Journal Volume
16
Journal Issue
17
Pages
4411-4420
Date Issued
2010
Author(s)
Hu M.-K.
Juan H.-F.
Shih Y.-Y.
Wang B.-J.
Chang C.L.
Huang S.-F.
Tsay Y.-G.
Lin K.-H.
Abstract
Purpose: 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. Experimental Design: 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-NH2-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 γ-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-NH2-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. ?2010 AACR.
SDGs
Other Subjects
calreticulin; gamma secretase; Notch1 receptor; stress activated protein kinase; animal experiment; animal model; article; cancer model; confocal microscopy; controlled study; correlation analysis; drug targeting; female; human; human cell; human tissue; immunohistochemistry; major clinical study; male; mouse; nerve cell differentiation; neuroblastoma; nonhuman; oncogene c myb; priority journal; prognosis; protein expression; reverse transcription polymerase chain reaction; signal transduction; survival rate; tumor xenograft; Western blotting; Amyloid Precursor Protein Secretases; Animals; Anthracenes; Blotting, Western; Calreticulin; Cell Differentiation; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Kaplan-Meier Estimate; Mice; Mice, Nude; Microscopy, Confocal; Neuroblastoma; Oligopeptides; Predictive Value of Tests; Prognosis; Receptor, Notch1; RNA Interference; Signal Transduction; Xenograft Model Antitumor Assays
Type
journal article