期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 8, 页码 4301-4319出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI134930
关键词
-
资金
- National Natural Science Foundation of China [81272651, 81570180, 81421003, 81770523, 81472402]
- State Key Laboratory of Cancer Biology [CBSKL2014Z07]
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSI(4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct downstream transcriptional target of Delta Np63 alpha, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the beta-catenin signaling pathway through direct phosphorylation of GSK-3 beta at Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improved radiosensitivity in both nude mouse and patient-derived xenograft models. Collectively, our results strongly suggest that the Delta Np63 alpha/RSK4/GSK-3 beta axis plays a Icey role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据