Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
Department of Surgery, Zhaoqing Medical College, Guangdong, 526070, China.
Cell Oncol (Dordr). 2023 Jun;46(3):571-587. doi: 10.1007/s13402-022-00761-x. Epub 2022 Dec 29.
Ezrin, known as a crosslinker between the plasma membrane and actin cytoskeleton, is closely associated with breast cancer (BC) progression. Here, we explored a novel role of ezrin in breast cancer liver metastasis (BCLM).
The clinical relevance of ezrin was evaluated using in silico tools and confirmed in BC specimens. The effect of ezrin on proliferation, migration and invasion was examined in vitro and in vivo using murine primary liver-metastatic breast cancer cells (mLM). The molecular mechanism involved in ezrin-mediated activation of the Notch1 signaling pathway was elucidated using in vitro models.
Data-mining demonstrated that ezrin mRNA and protein expression is up-regulated in breast cancer cohorts and has prognostic significance. Ezrin overexpression promotes cell proliferation, migration and invasion in vitro and in vivo. Hairy and enhancer of split-1 (Hes1) is one of the most significantly enriched candidates of differentially expressed genes in ezrin overexpression and control mLM cells. Ezrin can positively regulate Hes1 mRNA and protein expression, and their coexpression was associated with poor prognosis in BC patients. Ezrin promoted BC cell proliferation in a Hes1-dependent manner without directly interacting with Hes1. The functional link between ezrin and Hes1 is dependent on Notch1 activation through promotion of furin-like convertase cleavage.
Our results demonstrated that ezrin drives BCLM through activation of the Notch signaling pathway via furin-like convertase. These findings provide a better understanding of the mechanism of ezrin in breast cancer progression, with the goal of discovering a novel target for the treatment of BCLM in the future.
Ezrin 作为质膜和肌动蛋白细胞骨架之间的连接蛋白，与乳腺癌（BC）的进展密切相关。在这里，我们探讨了 Ezrin 在乳腺癌肝转移（BCLM）中的新作用。
使用计算机工具评估 Ezrin 的临床相关性，并在 BC 标本中进行验证。使用鼠原代肝转移性乳腺癌细胞（mLM）在体外和体内研究 Ezrin 对增殖、迁移和侵袭的影响。使用体外模型阐明 Ezrin 介导的 Notch1 信号通路激活的分子机制。
数据挖掘表明 Ezrin mRNA 和蛋白表达在乳腺癌队列中上调，具有预后意义。Ezrin 过表达促进体外和体内细胞增殖、迁移和侵袭。Hairy and enhancer of split-1 (Hes1) 是 Ezrin 过表达和对照 mLM 细胞中差异表达基因中最显著富集的候选基因之一。Ezrin 可以正向调节 Hes1 mRNA 和蛋白表达，其共表达与 BC 患者的预后不良相关。Ezrin 以 Hes1 依赖的方式促进 BC 细胞增殖，而不与 Hes1 直接相互作用。Ezrin 和 Hes1 之间的功能联系依赖于 Notch1 激活，通过促进 furin 样转化酶切割。
我们的结果表明，Ezrin 通过 furin 样转化酶激活 Notch 信号通路驱动 BCLM。这些发现为进一步研究 Ezrin 在乳腺癌进展中的机制提供了更好的理解，以期发现治疗 BCLM 的新靶点。
