下调和上调
癌症研究
癌变
基因沉默
乳腺肿瘤
Oncomir公司
泛素连接酶
转移
乳腺癌
泛素
生物
癌症
医学
内科学
生物化学
基因
作者
Min Cong,Yuan Wang,Yang Yang,Cheng Lian,Xueqian Zhuang,Xiaoxun Li,Peiyuan Zhang,Yingjie Liu,Jun Tang,Qifeng Yang,Xue Zhang,Hua Xiong,Ronggui Hu,Guohong Hu
出处
期刊:Nature cancer
[Springer Nature]
日期:2020-01-20
卷期号:1 (2): 222-234
被引量:16
标识
DOI:10.1038/s43018-019-0021-y
摘要
Tumor-initiating cells (TICs) are considered the culprits of cancer development and progression. Dysregulation of metastasis suppressor protein 1 (MTSS1) has been widely observed in tumor metastasis, but its functional contribution and mechanism in cancer is poorly understood. Here we report a role of MTSS1 in suppressing TICs in breast cancer. Mtss1 knockout (KO) enhances the mammary epithelial TIC subpopulation in both luminal and basal-like breast cancer mouse models. MTSS1 also suppresses tumorsphere formation in breast cancer cells. Mechanistically, MTSS1 interacts with the E3 ligase RanBP2-type and C3HC4-type zinc finger containing 1 (RBCK1) to facilitate RBCK1-mediated p65 ubiquitination and degradation, thus suppressing the NF-κB signaling pathway and tumorigenesis. In addition, actin beta-like 2 (ACTBL2) competes with RBCK1 for MTSS1 binding, leading to p65 stabilization. Importantly, MTSS1 silencing promotes patient-derived organoid formation and xenograft growth. MTSS1 downregulation in clinical tumors is also linked to worse prognosis. Overall our data reveal a new paradigm of NF-κB regulation and may have important implications in therapeutics targeting TICs. Cong et al. show that MTSS1 suppresses breast cancer initiation by promoting ubiquitin-mediated suppression of the NF-κB pathway. Loss of this regulatory mechanism promotes the activation and expansion of tumor-initiating cells.
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