Yap1 promotes the survival and self-renewal of breast tumor initiating cells via inhibiting Smad3 signaling.
Yap1 promotes the survival and self-renewal of breast tumor initiating cells via inhibiting Smad3 signaling.
复制标题
Yap1通过抑制Smad3信号促进乳腺肿瘤起始细胞的存活和自我更新
DOI：
10.18632/oncotarget.6655
复制
发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Diehn M
中科院分区：
文献类型：
--
作者：
Sun JG;Chen XW;Zhang LP;Wang J;Diehn M
肿瘤起始细胞（Tumor initiating cells，TIC）是肿瘤生长的根源。在MMTV-Wnt 1小鼠模型的自发性乳腺肿瘤中鉴定出TIC后，我们证实了TIC内Yap 1的特异性表达和活化。为了研究Yap 1在乳腺TIC自我更新中的作用及其潜在机制，我们将CD 49 fhighEpCAM低细胞分选为乳腺TIC。在乳腺TIC中异位表达的活性Yap 1促进其体外集落形成（p< 0.01）和体内自我更新（p< 0.01），并导致TIC频率增加4倍（p< 0.05）。重建条件性敲除小鼠以产生Yap 1敲除乳腺肿瘤。Yap 1的缺失导致乳腺TIC在体外（p< 0.01）和体内（p< 0.01）的显著生长劣势，并且它还导致TIC频率降低超过200倍（p< 0.01）。活性Yap 1的表达与磷酸化Smad 3（p-Smad 3）的表达呈负相关。转化生长因子β（Transforming growth factor β，TGF-β）可增强Smad 3的表达，抑制TIC的克隆形成。SIS 3是Smad 3的特异性抑制剂，它的存在可以挽救TGF-β诱导的细胞生长抑制，并逆转Yap 1对Smad 3的抑制作用。对包含2，072例人类乳腺癌样本的数据库的分析表明，Yap 1的高表达与患者的15年生存率和中位总生存率（mOS）的较差结果相关，特别是在那些没有雌激素受体1（ER）表达的基底乳腺肿瘤患者中。研究结果表明，活性Yap 1通过抑制Smad 3信号传导促进乳腺TIC的自我更新。
Tumor initiating cells (TICs) serve as the root of tumor growth. After identifying TICs in spontaneous breast tumors of the MMTV-Wnt1 mouse model, we confirmed the specific expression and activation of Yes-associated protein 1 (Yap1) within TICs. To investigate the role of Yap1 in the self-renewal of breast TICs and the underlying mechanism, we sorted CD49fhighEpCAMlow cells as breast TICs. Active Yap1 with ectopic expression in breast TICs promoted their colony formation in vitro (p< 0.01) and self-renewal in vivo (p< 0.01), and led to a 4-fold increase in TIC frequency (p< 0.05). A conditional knock-out mouse was reconstructed to generate Yap1 knock-out breast tumors. The loss of Yap1 led to a dramatic growth disadvantage of breast TICs in vitro (p< 0.01) and in vivo (p< 0.01), and it also led to an over 200-fold decrease in TIC frequency (p< 0.01). The expression of active Yap1 was negatively correlated with that of phosphorylated Smad3 (p-Smad3). Transforming growth factor β (TGF-β) served as a strong enhancer of Smad3 and an inhibitor of clonogenesis of TICs. The presence of SIS3, a specific inhibitor of Smad3, could rescue the TGF-β -induced growth inhibition and reverse the Smad3 inhibition by Yap1. Analysis of a database containing 2,072 human breast cancer samples showed that higher expressions of Yap1 correlated with a poorer outcome of a 15-year survival rate and median overall survival (mOS)in patients, especially in those with basal breast tumors without estrogen receptor 1 (ER) expression. The findings indicate that active Yap1 promotes the self-renewal of breast TICs by inhibiting Smad3 signaling.