Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer.
Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer.
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DOI：
10.3390/cancers12092372
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发表时间：
2020-08-21
期刊：
影响因子：
5.2
通讯作者：
Raman D
中科院分区：
文献类型：
--
作者：
Subramaniyan B;Sridharan S;M Howard C;M C Tilley A;Basuroy T;de la Serna I;Butt E;Raman D
CXCL 12-CXCR 4轴在乳腺癌转移的许多步骤中起着至关重要的作用，但其分子机制尚未完全阐明。我们以前报道过CXCL 12激活CXCR 4可促进LASP 1（LIM和SH 3蛋白1）的核定位。然后，核LASP 1与三阴性乳腺癌（TNBC）细胞系中的Snail 1相互作用。在这项研究中，我们报告说，Snail 1的核积累和保留依赖于由活性CXCR 4驱动的核LASP 1水平的增加。CXCR 4-LASP 1轴可能通过上调pS473-Akt、pS 9-GSK-3β、A20和LSD 1的核水平直接调节核Snail 1的稳定。此外，CXCR 4的激活诱导LASP 1与Snail 1、A20、GSK-3β和LSD 1的内源性结合。因此，核LASP 1也可以调节蛋白质-蛋白质相互作用，促进蜗牛1的稳定性。LASP 1的基因消融导致核Snail 1的错误定位，TNBC细胞侵袭Matrigel的能力丧失以及上皮和间充质标志物的表达失调，包括ALDH 1A 1（上皮乳腺癌干细胞样细胞的标志物）的表达增加。我们的研究结果揭示了CXCR 4-LASP 1轴在促进核定位Snail 1稳定性方面的新作用。
The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.
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影响因子：
6.2
作者：
Brenot A;Knolhoff BL;DeNardo DG;Longmore GD
通讯作者：
Longmore GD
影响因子：
5.3
作者：
Fras, Alex;Lambies, Guillem;Diaz, Victor M.
通讯作者：
Diaz, Victor M.
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
DOI：
10.29271/jcpsp.2019.03.240
发表时间：
2019-03-01
影响因子：
1
作者：
Cai, Fenglin;Xiao, Hualin;Tang, Jinhai
通讯作者：
Tang, Jinhai
影响因子：
2.3
作者：
Chen, Victor E.;Gillespie, Erin F.;Einck, John P.
通讯作者：
Einck, John P.