https://scholars.lib.ntu.edu.tw/handle/123456789/467194
標題: | Notch1 expression predicts an unfavorable prognosis and serves as a therapeutic target of patients with neuroblastoma | 作者: | HSIU-HAO CHANG HSIN-YU LEE Hu M.-K. PO-NIEN TSAO Juan H.-F. MIN-CHUAN HUANG Shih Y.-Y. Wang B.-J. YUNG-MING JENG Chang C.L. Huang S.-F. Tsay Y.-G. FON-JOU HSIEH Lin K.-H. WEN-MING HSU HSUEH-FEN JUAN |
公開日期: | 2010 | 卷: | 16 | 期: | 17 | 起(迄)頁: | 4411-4420 | 來源出版物: | Clinical Cancer Research | 摘要: | 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. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-77956256647&doi=10.1158%2f1078-0432.CCR-09-3360&partnerID=40&md5=48deae269346d5b13cd116c029077402 https://scholars.lib.ntu.edu.tw/handle/123456789/467194 |
ISSN: | 1078-0432 | DOI: | 10.1158/1078-0432.CCR-09-3360 | SDG/關鍵字: | 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 |
顯示於: | 解剖學暨細胞生物學科所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。