School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 561113, China; Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Toxicology. 2024 Sep;507:153886. doi: 10.1016/j.tox.2024.153886. Epub 2024 Jul 14.
Benzo[a]pyrene (BaP) is associated with the development of lung cancer, but the underlying mechanism has not been completely clarified. Here, we used 10 μM BaP to induce malignant transformation of human bronchial epithelial BEAS-2B cells, named BEAS-2B-T. Results indicated that BaP (6.25, 12.5 and 25 μM) treatment significantly promoted the migration and invasion of BEAS-2B-T cells. Meanwhile, BaP exposure inhibited ferroptosis in BEAS-2B-T, ferroptosis-related indexes Fe, malondialdehyde (MDA), lipid peroxidation (LPO) and reactive oxygen species (ROS) decreased significantly. The protein level of ferroptosis-related molecule transferrin receptor (TFRC) decreased significantly, while solute carrier family 7 membrane 11 (SLC7A11), ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) increased significantly. The intervention of ferroptosis dramatically effected the migration and invasion of BEAS-2B-T induced by BaP. Furthermore, the expression of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) was markedly increased after BaP exposure. YTHDF1 knockdown inhibited BEAS-2B-T migration and invasion by promoting ferroptosis. In the meantime, the contents of Fe, MDA, LPO and ROS increased significantly, TFRC was markedly increased, and SLC7A11, FTH1, and GPX4 were markedly decreased. Moreover, overexpression of YTHDF1 promoted BEAS-2B-T migration and invasion by inhibiting ferroptosis. Importantly, knockdown of YTHDF1 promoted ferroptosis and reduced BEAS-2B-T migration and invasion during BaP exposure, and overexpression of YTHDF1 increased migration and invasion of BEAS-2B-T by inhibiting ferroptosis during BaP exposure. RNA immunoprecipitation assays indicated that the binding of YTHDF1 to SLC7A11 and FTH1 markedly increased after YTHDF1 overexpression. Therefore, we concluded that BaP promotes the malignant progression of BEAS-2B-T cells through YTHDF1 upregulating SLC7A11 and FTH1 to inhibit ferroptosis. This study reveals new epigenetic and ferroptosis markers for preventing and treating lung cancer induced by environmental carcinogens.
苯并[a]芘（BaP）与肺癌的发生发展有关，但其中的作用机制尚未完全阐明。在这里，我们使用 10μM BaP 诱导人支气管上皮 BEAS-2B 细胞发生恶性转化，命名为 BEAS-2B-T。结果表明，BaP（6.25、12.5 和 25μM）处理显著促进了 BEAS-2B-T 细胞的迁移和侵袭。同时，BaP 暴露抑制了 BEAS-2B-T 中的铁死亡，铁死亡相关指标铁、丙二醛（MDA）、脂质过氧化（LPO）和活性氧（ROS）显著降低。铁死亡相关分子转铁蛋白受体（TFRC）的蛋白水平显著降低，而溶质载体家族 7 膜 11（SLC7A11）、铁蛋白重链 1（FTH1）和谷胱甘肽过氧化物酶 4（GPX4）显著增加。铁死亡的干预显著影响了 BaP 诱导的 BEAS-2B-T 的迁移和侵袭。此外，BaP 暴露后 YTH N6-甲基腺苷 RNA 结合蛋白 1（YTHDF1）的表达明显增加。YTHDF1 敲低通过促进铁死亡抑制 BEAS-2B-T 的迁移和侵袭。同时，Fe、MDA、LPO 和 ROS 的含量显著增加，TFRC 明显增加，SLC7A11、FTH1 和 GPX4 明显减少。此外，YTHDF1 的过表达通过抑制铁死亡促进 BEAS-2B-T 的迁移和侵袭。重要的是，YTHDF1 的敲低促进了 BaP 暴露时 BEAS-2B-T 的铁死亡，并减少了迁移和侵袭，而过表达 YTHDF1 通过抑制铁死亡增加了 BEAS-2B-T 在 BaP 暴露时的迁移和侵袭。RNA 免疫沉淀分析表明，YTHDF1 过表达后 SLC7A11 和 FTH1 与 YTHDF1 的结合明显增加。因此，我们得出结论，BaP 通过上调 YTHDF1 抑制铁死亡促进 BEAS-2B-T 细胞的恶性进展。这项研究为预防和治疗环境致癌物诱导的肺癌提供了新的表观遗传和铁死亡标志物。
