Department of Life Science, Dongguk University-Seoul, Biomedi Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang 10326, Gyeonggi-do, Republic of Korea.
Int J Mol Sci. 2023 Mar 24;24(7):6157. doi: 10.3390/ijms24076157.
Toluene diisocyanate (TDI) is commonly used in manufacturing, and it is highly reactive and causes respiratory damage. This study aims to identify the mechanism of tumorigenesis in bronchial epithelial cells induced by chronic TDI exposure. In addition, transcriptome analysis results confirmed that TDI increases transforming growth factor-beta 1 (TGF-β1) expression and regulates genes associated with cancerous characteristics in bronchial cells. Our chronically TDI-exposed model exhibited elongated spindle-like morphology, a mesenchymal characteristic. Epithelial-mesenchymal transition (EMT) was evaluated following chronic TDI exposure, and EMT biomarkers increased concentration-dependently. Furthermore, our results indicated diminished cell adhesion molecules and intensified cell migration and invasion. In order to investigate the cellular regulatory mechanisms resulting from chronic TDI exposure, we focused on TGF-β1, a key factor regulated by TDI exposure. As predicted, TGF-β1 was significantly up-regulated and secreted in chronically TDI-exposed cells. In addition, SMAD2/3 was also activated considerably as it is the direct target of TGF-β1 and TGF-β1 receptors. Inhibiting TGF-β1 signaling through blocking of the TGF-β receptor attenuated EMT and cell migration in chronically TDI-exposed cells. Our results corroborate that chronic TDI exposure upregulates TGF-β1 secretion, activates TGF-β1 signal transduction, and leads to EMT and other cancer properties.
甲苯二异氰酸酯（TDI）常用于制造，具有高度反应性，会造成呼吸道损伤。本研究旨在确定慢性 TDI 暴露诱导支气管上皮细胞致癌的机制。此外，转录组分析结果证实，TDI 增加转化生长因子-β1（TGF-β1）的表达，并调节支气管细胞中与癌变特征相关的基因。我们的慢性 TDI 暴露模型表现出伸长的纺锤形形态，具有间充质特征。在慢性 TDI 暴露后评估上皮-间充质转化（EMT），EMT 生物标志物呈浓度依赖性增加。此外，我们的结果表明细胞黏附分子减少，细胞迁移和侵袭增强。为了研究慢性 TDI 暴露导致的细胞调节机制，我们专注于 TGF-β1，这是 TDI 暴露调节的关键因素。正如预测的那样，慢性 TDI 暴露细胞中 TGF-β1 显著上调并分泌。此外，SMAD2/3 也被显著激活，因为它是 TGF-β1 和 TGF-β1 受体的直接靶标。通过阻断 TGF-β 受体抑制 TGF-β1 信号通路可减弱慢性 TDI 暴露细胞中的 EMT 和细胞迁移。我们的结果证实，慢性 TDI 暴露上调 TGF-β1 分泌，激活 TGF-β1 信号转导，并导致 EMT 和其他癌症特性。
