苯并[a]芘（BaP）与肺癌的发生有关，但其潜在机制尚未完全阐明。在这里，我们使用10μM BaP诱导人支气管上皮BEAS-2B细胞恶性转化，命名为BEAS-2B-T。结果表明，BaP（6.25、12.5和25μM）处理显着促进BEAS-2B-T细胞的迁移和侵袭。同时，BaP暴露抑制了BEAS-2B-T的铁死亡，铁死亡相关指标Fe2+、丙二醛（MDA）、脂质过氧化（LPO）和活性氧（ROS）显着降低。铁死亡相关分子转铁蛋白受体（TFRC）的蛋白水平显着下降，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）的蛋白水平显着升高。铁死亡的干预显着影响BaP诱导的BEAS-2B-T的迁移和侵袭。此外，暴露于 BaP 后，YTH N6-甲基腺苷 RNA 结合蛋白 1 (YTHDF1) 的表达显着增加。 YTHDF1 敲低通过促进铁死亡来抑制 BEAS-2B-T 迁移和侵袭。同时，Fe2+、MDA、LPO、ROS含量显着升高，TFRC显着升高，SLC7A11、FTH1、GPX4显着降低。此外，YTHDF1的过表达通过抑制铁死亡促进BEAS-2B-T迁移和侵袭。重要的是，在 BaP 暴露期间，YTHDF1 的敲低促进了铁死亡并减少了 BEAS-2B-T 的迁移和侵袭，而 YTHDF1 的过表达通过在 BaP 暴露期间抑制铁死亡来增加 BEAS-2B-T 的迁移和侵袭。 RNA免疫沉淀分析表明，YTHDF1过表达后，YTHDF1与SLC7A11和FTH1的结合显着增加。因此，我们得出结论，BaP通过YTHDF1上调SLC7A11和FTH1抑制铁死亡来促进BEAS-2B-T细胞的恶性进展。这项研究揭示了用于预防和治疗环境致癌物诱发的肺癌的新表观遗传和铁死亡标记。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Benzo[a]pyrene (BaP) is associated with the development of lung cancer, but the underlying mechanism has not been completely clarified. Here, we used 10μM 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 25μM) treatment significantly promoted the migration and invasion of BEAS-2B-T cells. Meanwhile, BaP exposure inhibited ferroptosis in BEAS-2B-T, ferroptosis-related indexes Fe2+, 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 Fe2+, 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 of 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.Copyright © 2024 Elsevier B.V. All rights reserved.