KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties.
KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties.
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KRT19直接与β-catenin/rac1复合物相互作用，以调节麻木依赖性凹槽信号通路和乳腺癌特性。
DOI：
10.1038/onc.2016.221
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发表时间：
2017-01-19
期刊：
影响因子：
8
通讯作者：
Cho SG
中科院分区：
文献类型：
--
作者：
Saha SK;Choi HY;Kim BW;Dayem AA;Yang GM;Kim KS;Yin YF;Cho SG
研究表明，角蛋白(keratins，Krt)与其他蛋白质之间的相互作用启动了调节细胞迁移、侵袭和转移的信号级联反应。在目前的研究中，我们发现KRT19在乳腺癌中的表达特别高，并且与其侵袭性显著相关。此外，KRT19基因的敲除导致乳腺癌细胞的增殖、迁移、侵袭、耐药和球体形成增加，这是通过上调的Notch信号通路实现的。这是由于Numb的表达减少，Numb是Noch信号通路的抑制蛋白。此外，我们还发现KRT19能与β-连环蛋白/RAC1复合体相互作用，增强β-连环蛋白的核转位。相应地，KRT19基因的敲除抑制了β-连环蛋白的核转位以及β-连环蛋白介导的Numb的表达。此外，KRT19介导的Numb和NOTCH1表达的调节导致乳腺癌患者来源的CD133High/CXCR4High/ALDH1高表达的肿瘤干细胞(CSLC)的肿瘤干细胞特性受到抑制，这些CSLC表现出非常低的KRT19和高表达的NOTCH1。综上所述，我们的研究提示KRT19在调节β-连环蛋白/RAC1复合体的核输入中具有新的功能，从而调节乳腺癌和CSLC中数量依赖的Noch信号通路，这可能对癌症或CSLC的治疗具有潜在的临床意义。
Studies have reported that interactions between keratins (KRTs) and other proteins initiate signaling cascades that regulate cell migration, invasion, and metastasis. In the current study, we found that expression of KRT19 was specifically high in breast cancers and significantly correlated with their invasiveness. Moreover, knockdown of KRT19 led to increased proliferation, migration, invasion, drug resistance, and sphere formation in breast cancer cells via an upregulated NOTCH signaling pathway. This was owing to reduced expression of NUMB, an inhibitory protein of the NOTCH signaling pathway. In addition, we found that KRT19 interacts with β-catenin/RAC1 complex and enhances the nuclear translocation of β-catenin. Concordantly, knockdown of KRT19 suppressed the nuclear translocation of β-catenin as well as β-catenin-mediated NUMB expression. Furthermore, modulation of KRT19-mediated regulation of NUMB and NOTCH1 expression led to the repression of the cancer stem cell properties of breast cancer patient-derived CD133high/CXCR4high/ALDH1high cancer stem-like cells (CSLCs), which showed very low KRT19 and high NOTCH1 expression. Taken together, our study suggests a novel function for KRT19 in the regulation of nuclear import of the β-catenin/RAC1 complex, thus modulating the NUMB-dependent NOTCH signaling pathway in breast cancers and CSLCs, which might bear potential clinical implications for cancer or CSLC treatment.