文章目录

MTSS1通过增强rbck1介导的p65泛素化抑制乳腺肿瘤启动细胞

原文发布日期：2020-01-20

英文摘要：

摘要翻译：

原文链接：

文章：

MTSS1通过增强rbck1介导的p65泛素化抑制乳腺肿瘤启动细胞

MTSS1 suppresses mammary tumor-initiating cells by enhancing RBCK1-mediated p65 ubiquitination

原文发布日期：2020-01-20

英文摘要：

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.

摘要翻译：

肿瘤起源细胞(TICs)被认为是癌症进展和发展的罪魁祸首。转移抑制素1(MTSS1)的失衡状态在肿瘤转移中被广泛观察到，但在癌症中的功能作用及其机制尚不完全清楚。本研究报道MTSS1在乳腺癌中抑制TICs的作用。MTSS1敲除小鼠模型中增殖性上皮TIC亚群体在基底样和乳头状乳腺癌模型中增加。MTSS1还抑制乳腺癌细胞瘤云的形成。机制上，MTSS1与RanBP2型和C3HC4型锌指含有1(RBCK1)蛋白相互作用，促进RBCK1介导的p65泛素化和降解，从而抑制NF-κB信号通路及肿瘤发生。此外，ACTBL2（α-actin-like 2）与RBCK1竞争MTSS1结合，导致p65稳定。重要的是，MTSS1沉默促进患者来源器官小体形成和异物瘤生长。临床肿瘤中MTSS1的降表达也与预后不良相关。综上所述，我们发现NF-κB调控的新范式，并且在治疗TICs靶向药物中具有重要意义。