克拉斯
JAG1
结直肠癌
癌症研究
癌症
大肠癌小鼠模型的建立
Notch信号通路
肿瘤进展
生物
信号转导
医学
内科学
细胞生物学
作者
Maria Pelullo,Francesca Nardozza,Sabrina Zema,Roberta Quaranta,Carmine Nicoletti,Zein Mersini Besharat,María Pía Felli,Bruna Cerbelli,Giulia d’Amati,Rocco Palermo,Carlo Capalbo,Claudio Talora,Lucia Di Marcotullio,Giuseppe Giannini,Saula Checquolo,Isabella Screpanti,Diana Bellavia
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2019-11-01
卷期号:79 (21): 5575-5586
被引量:25
标识
DOI:10.1158/0008-5472.can-19-0145
摘要
Colorectal cancer is characterized by well-known genetic defects and approximately 50% of cases harbor oncogenic Ras mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including colorectal cancer, and correlates with cancer progression, poor prognosis, and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in colorectal cancer tumors with mutant Kras, which ultimately triggered intrinsic reverse signaling via its nuclear-targeted intracellular domain Jag1-ICD. This process occurred when Kras/Erk/ADAM17 signaling was switched on, demonstrating that Jagged1 is a novel target of the Kras signaling pathway. Notably, Jag1-ICD promoted tumor growth and epithelial-mesenchymal transition, enhancing colorectal cancer progression and chemoresistance both in vitro and in vivo. These data highlight a novel role for Jagged1 in colorectal cancer tumor biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as an oncogenic driver that is able to sustain tumor pathogenesis and to confer chemoresistance through a noncanonical mechanism. SIGNIFICANCE: These findings present a novel role of the transcriptionally active Jag1-ICD fragment to confer and mediate some of the activity of oncogenic KRAS.
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