Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2217-14 Hayashi-Cho, Takamatsu, Kagawa, 761-0395, Japan.
Cell Commun Signal. 2024 Aug 8;22(1):392. doi: 10.1186/s12964-024-01775-8.
Epithelial-mesenchymal transition (EMT) is a cellular process in embryonic development, wound healing, organ fibrosis, and cancer metastasis. Previously, we and others have reported that proinflammatory cytokine interleukin-1β (IL-1β) induces EMT. However, the exact mechanisms, especially the signal transduction pathways, underlying IL-1β-mediated EMT are not yet completely understood. Here, we found that IL-1β stimulation leads to the partial EMT-like phenotype in human lung epithelial A549 cells, including the gain of mesenchymal marker (vimentin) and high migratory potential, without the complete loss of epithelial marker (E-cadherin). IL-1β-mediated partial EMT induction was repressed by PI3K inhibitor LY294002, indicating that the PI3K/AKT pathway plays a significant role in the induction. In addition, ERK1/2 inhibitor FR180204 markedly inhibited the IL-1β-mediated partial EMT induction, demonstrating that the MEK/ERK pathway was also involved in the induction. Furthermore, we found that the activation of the PI3K/AKT and MEK/ERK pathways occurred downstream of the epidermal growth factor receptor (EGFR) pathway and the IL-1 receptor (IL-1R) pathway, respectively. Our findings suggest that the PI3K/AKT and MEK/ERK pathways coordinately promote the IL-1β-mediated partial EMT induction. The inhibition of not one but both pathways is expected yield clinical benefits by preventing partial EMT-related disorders such as organ fibrosis and cancer metastasis.
上皮-间充质转化 (EMT) 是胚胎发育、创伤愈合、器官纤维化和癌症转移过程中的一个细胞过程。以前，我们和其他人已经报道了促炎细胞因子白细胞介素-1β (IL-1β) 诱导 EMT。然而，IL-1β 介导的 EMT 的确切机制，特别是信号转导途径，尚未完全了解。在这里，我们发现 IL-1β 刺激导致人肺上皮 A549 细胞出现部分 EMT 样表型，包括获得间充质标志物（波形蛋白）和高迁移能力，而上皮标志物（E-钙黏蛋白）并未完全丧失。PI3K 抑制剂 LY294002 抑制了 IL-1β 介导的部分 EMT 诱导，表明 PI3K/AKT 途径在诱导中起重要作用。此外，ERK1/2 抑制剂 FR180204 显著抑制了 IL-1β 介导的部分 EMT 诱导，表明 MEK/ERK 途径也参与了诱导。此外，我们发现 PI3K/AKT 和 MEK/ERK 途径的激活分别发生在表皮生长因子受体 (EGFR) 途径和白细胞介素-1 受体 (IL-1R) 途径的下游。我们的研究结果表明，PI3K/AKT 和 MEK/ERK 途径协同促进了 IL-1β 介导的部分 EMT 诱导。抑制不仅一条途径，而是两条途径，有望通过防止器官纤维化和癌症转移等与部分 EMT 相关的疾病，产生临床获益。
