An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness
Publication in refereed journal

香港中文大學研究人員
替代計量分析
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其它資訊
摘要Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.
出版社接受日期01.05.2021
著者Lei Liu, Tianyu Tao, Shihua Liu, Xia Yang, Xuwei Chen, Jiaer Liang, Ruohui Hong, Wenting Wang, Yi Yang, Xiaoyi Li, Youhong Zhang, Quanfeng Li, Shujun Liang, Haocheng Yu, Yun Wu, Xinyu Guo, Yan Lai, Xiaofan Ding, Hongyu Guan, Jueheng Wu, Xun Zhu, Jie Yuan, Jun Li, Shicheng Su, Mengfeng Li, Xiuyu Cai, Junchao Cai, Han Tian
期刊名稱Nature Communications
出版年份2021
月份5
日期11
卷號12
期次1
文章號碼2693
國際標準期刊號2041-1723
語言美式英語

上次更新時間 2021-03-12 於 00:40