MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis
MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis
复制标题
MAP2K4与Vimentin相互作用激活PI3K/AKT通路促进乳腺癌发病
DOI：
10.18632/aging.102485
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发表时间：
2019-11-30
期刊：
影响因子：
5.2
通讯作者：
Li, Rong
中科院分区：
文献类型：
--
作者：
Liu, Shu;Huang, Juan;Li, Rong
丝裂原激活蛋白激酶激酶 4 (MAP2K4) 是丝裂原激活蛋白激酶 (MAPK) 激活剂家族的成员。 MAPK 信号在细胞增殖、分化、转录调控和发育中发挥着重要作用。然而，MAP2K4在乳腺癌中的具体功能和机制尚未阐明。根据我们的研究，乳腺癌细胞中过表达的 MAP2K4 增加了体内和体外的增殖、迁移和侵袭，而 MAP2K4 敲低则恢复了这些效果。随后的机制分析表明，MAP2K4 通过激活磷酸肌醇 3 激酶 (PI3K)/AKT 信号、下游蛋白、c-JUN、G1/S 细胞周期和上皮间质转化 (EMT) 来促进细胞增殖、迁移和侵袭。同时，MAP2K4与Vimentin相互作用并进一步传播恶性表型。此外，MAP2K4 和 Vimentin 表达水平高的患者的总体生存率比这两种蛋白表达水平低的患者较差。我们的研究表明，MAP2K4有可能作为乳腺癌的癌基因，它激活磷酸化的PI3K/AKT信号通路，激活下游周期相关蛋白和EMT信号，同时与波形蛋白相互作用，促进乳腺癌细胞的增殖、迁移和侵袭。在我们的研究中，MAP2K4和Vimentin共表达被证实是乳腺癌的不利因素。
Mitogen-activated protein kinase kinase 4 (MAP2K4) is a member of the mitogen-activated protein kinase (MAPK) activator family. MAPK signaling plays a significant role in cell proliferation, differentiation, transcriptional regulation, and development. However, specific function and mechanism of MAP2K4 in breast cancer have not been clarified. According to our study, overexpressed MAP2K4 in breast cancer cells increased proliferation, migration, and invasion in vivo and in vitro, while MAP2K4 knockdown restored the effects. Subsequent mechanistic analyses demonstrated that MAP2K4 promoted cell proliferation, migration, and invasion by activating phosphoinositide-3-kinase (PI3K)/AKT signaling, the downstream proteins, c-JUN, the G1/S cell cycle, and the epithelial-to-mesenchymal transition (EMT). Meanwhile, MAP2K4 interacted with Vimentin and further propagated the malignant phenotype. Furthermore, patients with high MAP2K4 and Vimentin expression levels had poorer overall survival rates than those with low expression levels of both proteins. Our studies demonstrated that MAP2K4 has the potential to serve as an oncogene in breast cancer and it activates the phosphorylated PI3K/AKT signaling pathway to activate downstream cycle-associated proteins and EMT signals while interacting with Vimentin to promote breast cancer cells proliferation, migration, and invasion. In our study, MAP2K4 and Vimentin co-expression is confirmed to be an unfavorable factor in breast cancer.