Cell Cycle-Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A
Cell Cycle-Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A
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DOI：
10.1158/1541-7786.mcr-17-0417
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发表时间：
2018-01-01
影响因子：
5.2
通讯作者：
Maxwell, Christopher A.
中科院分区：
文献类型：
--
作者：
Chu, Tony L. H.;Connell, Marisa;Maxwell, Christopher A.
细胞周期进程和迁移表型的获得是人类癌细胞的标志，它们被认为是独立的过程，但可能通过控制中心体微管成核的分子途径相互连接。在此，细胞周期进展显著影响4 T1-转移酶2乳腺癌细胞在免疫活性BALB/c或免疫功能低下的NOD-SCID γ（NSG）小鼠中的植入动力学。伤口闭合试验的多参数成像用于跟踪表达荧光泛素细胞周期指示剂的上皮细胞或癌细胞中的细胞周期进展、细胞迁移和相关表型。在细胞周期的S-G（2）期，细胞迁移的速度和方向性增加，并且该期的细胞具有前极化中心体和增强的微管成核能力。抑制Aurora激酶-A（AURKA/Aurora-A）可抑制这些表型，而不改变细胞周期进程。在G（2）期，在透明质酸介导的运动受体（HMMR）沉默的细胞中，中心体磷酸化Aurora-A的水平降低，这是一种Aurora-A激活蛋白TPX 2的核转运。TPX 2的核转运依赖于HMMR-T703，其从核膜处与输入素-α（KPNA 2）的复合物中释放TPX 2。最后，磷酸化HMMR-T703（Aurora-A的底物）的丰度可预测雌激素受体（ER）阴性（n = 941）、三阴性（TNBC）表型（n = 538）或基底样亚型（n = 293）乳腺癌患者的乳腺癌特异性生存期和无复发生存期，但不能预测ER阳性乳腺癌患者（n = 2，218）。总之，这些数据表明Aurora-A/TPX 2/HMMR分子轴与细胞周期进程和细胞迁移相交。(C)2017年AACR。
Cell-cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell-cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multiparameter imaging of wound closure assays was used to track cell-cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell-cycle indicator. Cell migration occurred with an elevated velocity and directionality during the S-G(2)-phase of the cell cycle, and cells in this phase possess front-polarized centrosomes with augmented microtubule nucleation capacity. Inhibition of Aurora kinase-A (AURKA/Aurora-A) dampens these phenotypes without altering cell-cycle progression. During G(2)-phase, the level of phosphorylated Aurora-A at centrosomes is reduced in hyaluronan-mediated motility receptor (HMMR)-silenced cells as is the nuclear transport of TPX2, an Aurora-A-activating protein. TPX2 nuclear transport depends upon HMMR-T703, which releases TPX2 from a complex with importin-alpha (KPNA2) at the nuclear envelope. Finally, the abundance of phosphorylated HMMR-T703, a substrate for Aurora-A, predicts breast cancer-specific survival and relapse-free survival in patients with estrogen receptor (ER)-negative (n = 941), triple-negative (TNBC) phenotype (n = 538), or basal-like subtype (n = 293) breast cancers, but not in those patients with ER-positive breast cancer (n = 2,218). Together, these data demonstrate an Aurora-A/TPX2/HMMR molecular axis that intersects cell-cycle progression and cell migration. (C) 2017 AACR.