CUEDC2 Drives β-Catenin Nuclear Translocation and Promotes Triple-Negative Breast Cancer Tumorigenesis.
CUEDC2 Drives β-Catenin Nuclear Translocation and Promotes Triple-Negative Breast Cancer Tumorigenesis.
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CUEDC2 驱动β-连环蛋白核易位并促进三阴性乳腺癌肿瘤发生
作者：
Wnt 信号的过度激活对于肿瘤的形成至关重要。充分阐明癌症特异性 Wnt 信号通路如何激活或促进肿瘤发生的分子细节将有助于确定未来的治疗策略。在这里，我们的目的是探讨 CUEDC2（一种新型的含有 CUE 结构域的蛋白质）对 Wnt 信号传导激活和三阴性乳腺癌（TNBC）肿瘤发生的贡献，并确定其潜在机制。 TNBC 患者样本和无病生存 (DFS) 数据用于确定 CUEDC2 与 TNBC 进展之间的关联。在体外 TNBC 细胞和体内皮下异种移植肿瘤中检查了 CUEDC2 对 TNBC 的影响。采用基因敲低、免疫沉淀加液相色谱-串联质谱、pull-down、免疫共沉淀、局部表面等离子共振和核易位分析等方法揭示了CUEDC2调节Wnt信号传导和TNBC发展的机制。 CUEDC2 足以维持 TNBC 肿瘤发生所需的 Wnt 信号传导的过度激活。 CUEDC2 的贡献在确定体外和体内致癌 Wnt 信号转导的结果中发挥着重要作用。从机制上讲，CUEDC2中的CUE结构域直接与β-catenin中的ARM（7-9）结构域结合，促进β-catenin核转位并增强β-catenin靶基因的表达。更重要的是，针对 CUEDC2 中 CUE 结构域的 11 个氨基酸竞争性肽阻断了 CUEDC2 和 β-catenin 的相互作用，并在体外和体内消除了 TNBC 细胞的恶性表型。我们观察到，表现出较高 CUEDC2 水平的 TNBC 患者表现出 Wnt 信号通路显着过度激活和较差的临床结果，这凸显了我们研究结果的临床相关性。 CUEDC2 通过直接结合 β-catenin 增强 Wnt 信号传导并加速其核转位，从而促进 TNBC 肿瘤生长。针对 CUEDC2 和 β-catenin 的相互作用可能是对抗 TNBC 的一个有价值的策略。
Hyperactivation of Wnt signaling is crucial in tumor formation. Fully elucidating the molecular details of how the cancer-specific Wnt signaling pathway is activated or contributes to tumorigenesis will help in determining future treatment strategies. Here, we aimed to explore the contribution of CUEDC2, a novel CUE-domain-containing protein, to the activation of Wnt signaling and the tumorigenesis of triple-negative breast cancer (TNBC) and to determine the underlying mechanisms. TNBC patient samples and disease-free survival (DFS) data were used to determine the association between CUEDC2 and TNBC progression. The effects of CUEDC2 on TNBC were examined in TNBC cells in vitro and in subcutaneous xenograft tumors in vivo. Gene knockdown, immunoprecipitation plus liquid chromatography–tandem mass spectrometry, pull-down, co-immunoprecipitation, localized surface plasmon resonance, and nuclear translocation analysis were used to uncover the mechanisms of CUEDC2 in regulating Wnt signaling and TNBC development. CUEDC2 is sufficient to maintain the hyperactivation of Wnt signaling required for TNBC tumorigenesis. The contribution of CUEDC2 plays a major role in determining the outcome of oncogenic Wnt signaling both in vitro and in vivo. Mechanistically, the CUE domain in CUEDC2 directly bound to the ARM (7–9) domain in β-catenin, promoted β-catenin nuclear translocation and enhanced the expression of β-catenin targeted genes. More importantly, an 11-amino-acid competitive peptide targeting the CUE domain in CUEDC2 blocked the interactions of CUEDC2 and β-catenin and abrogated the malignant phenotype of TNBC cells in vitro and in vivo. We observed that TNBC patients who exhibited higher levels of CUEDC2 showed marked hyperactivation of the Wnt signaling pathway and poor clinical outcomes, highlighting the clinical relevance of our findings. CUEDC2 promotes TNBC tumor growth by enhancing Wnt signaling through directly binding to β-catenin and accelerating its nuclear translocation. Targeting the interactions of CUEDC2 and β-catenin may be a valuable strategy for combating TNBC.
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影响因子：
50.3
作者：
Zhang N;Wei P;Gong A;Chiu WT;Lee HT;Colman H;Huang H;Xue J;Liu M;Wang Y;Sawaya R;Xie K;Yung WK;Medema RH;He X;Huang S
通讯作者：
Huang S
CUEDC2通过抑制STAT3和NF-κB信号通路的激活来抑制胶质瘤致瘤性
影响因子：
5.2
作者：
Li F;Tang C;Jin D;Guan L;Wu Y;Liu X;Wu X;Wu QY;Gao D
通讯作者：
Gao D
影响因子：
15.9
作者：
Zhou, Cuiqi;Jiao, Yonghui;Melmed, Shlomo
通讯作者：
Melmed, Shlomo
DOI：
10.1073/pnas.1221009110
发表时间：
2013-07-02
影响因子：
11.1
作者：
Zhang, Wei-Na;Zhou, Jie;Li, Hui-Yan
通讯作者：
Li, Hui-Yan
影响因子：
82.9
作者：
Pan, Xin;Zhou, Tao;Zhang, Xue-Min
通讯作者：
Zhang, Xue-Min