國家衛生研究院 NHRI:Item 3990099045/4952
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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/4952


    Title: Notch1 expression predicts an unfavorable prognosis and serves as a therapeutic target of patients with neuroblastoma
    Authors: Chang, HH;Lee, HY;Hu, MK;Tsao, PN;Juan, HF;Huang, MC;Shih, YY;Wang, BJ;Jeng, YM;Chang, C;Huang, SF;Tsay, YG;Hsieh, FJ;Lin, KH;Hsu, WM;Liao, YF
    Contributors: Division of Molecular and Genomic Medicine
    Abstract: Purpose: Notch signaling has been implicated to play a critical role in the tumorigenesis of neuroblas-toma (NB) and can modulate calreticulin (CRT) expression that strongly correlates with tumor differen-tiation 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 inhi-bition of Notch signaling. This effect was mediated by a c-Jun-NH2-kinase–dependent pathway. Further-more, 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.
    Date: 2010-09
    Relation: Clinical cancer research. 2010 Sep;16(17):4411-4420.
    Link to: http://dx.doi.org/10.1158/1078-0432.ccr-09-3360
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-0432&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000281444700015
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77956256647
    Appears in Collections:[Shiu-Feng Kathy Huang] Periodical Articles

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