A novel PAK4-CEBPB-CLDN4 axis involving in breast cancer cell migration and invasion
A novel PAK4-CEBPB-CLDN4 axis involving in breast cancer cell migration and invasion
复制标题
一种参与乳腺癌细胞迁移和侵袭的新型 PAK4-CEBPB-CLDN4 轴
DOI：
10.1016/j.bbrc.2019.02.070
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发表时间：
2019-04-02
影响因子：
3.1
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Wang, Fei;Gao, Yunling;Li, Feng
紧密连接蛋白4（Claudin-4，CLDN 4）是紧密连接蛋白的重要成员，在乳腺癌细胞中异常表达，并有助于细胞迁移和侵袭。然而，控制乳腺癌中CLDN 4表达的机制知之甚少。在这里，我们报道了在人乳腺癌组织中CLDN 4的表达与p21激活激酶4（PAK 4）的表达呈正相关。在MDA-MB-231和ZR-75-30细胞中敲低PAK 4抑制CLDN 4表达并显著抑制细胞迁移和侵袭。相反，PAK 4敲低细胞中CLDN 4表达的恢复逆转了对迁移和侵袭的抑制。我们鉴定了CCAAT/增强子结合蛋白β（CEBPB）作为CLDN 4的新型转录调节因子，并证实CEBPB结合于CLDN 4启动子的-1093至-991 bp区域。重要的是，我们发现PAK 4增强了Thr-235上的CEBPB磷酸化。总之，我们发现PAK 4介导的CEBPB活化上调CLDN 4表达以促进乳腺癌细胞迁移和侵袭。我们的研究结果可能有助于理解CLDN 4的调控机制，并建议PAK 4-CEBPB-CLDN 4轴作为乳腺癌的潜在治疗靶点。(C)2019爱思唯尔公司All rights reserved.
Claudin-4 (CLDN4), a crucial member of tight junction proteins, is aberrantly expressed in breast cancer cells and contributes to cell migration and invasion. However, the mechanisms controlling CLDN4 expression in breast cancer are poorly understood. Here, we reported that CLDN4 expression correlated positively with p21-activated kinase 4 (PAK4) expression in human breast cancer tissues. Knockdown of PAK4 in MDA-MB-231 and ZR-75-30 cells suppressed CLDN4 expression and significantly inhibited cell migration and invasion. Conversely, restoration of CLDN4 expression in PAK4-knockdown cells reversed the inhibition of migration and invasion. We identified CCAAT/enhancer-binding protein beta (CEBPB) as a novel transcriptional regulator of CLDN4 and confirmed that CEBPB bound to the -1093 to -991 bp region of the CLDN4 promoter. Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr-235. In summary, we showed that PAK4-mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion. Our results might contribute to understanding the mechanisms of CLDN4 regulation and suggest PAK4-CEBPB-CLDN4 axis as a potential therapeutic target for breast cancer. (C) 2019 Elsevier Inc. All rights reserved.