苯并（a）pyrene通过调节yth n6--甲基腺苷RNA RNA结合蛋白1来促进恶性转化的BEAS-2B细胞的恶性进展
Benzo(a)pyrene promotes the malignant progression of malignant-transformed BEAS-2B cells by regulating YTH N6-methyladenosine RNA binding protein 1 to inhibit ferroptosis
影响因子:4.60000
分区:医学3区 / 药学2区 毒理学2区
发表日期:2024 Sep
作者:
Na Wang, Hong-Qiang Chen, Yong Zeng, Yu Shi, Zhe Zhang, Jiang-Ying Li, Shi-Meng Zhou, Ya-Wen Li, Shuang-Wu Deng, Xue Han, Zi-Yuan Zhou, Mao-Lin Yao, Wen-Bin Liu
摘要
苯并[A] pyrene（BAP）与肺癌的发展有关，但尚未完全阐明潜在的机制。在这里，我们使用10μMBAP诱导人支气管上皮Beas-2b细胞的恶性转化，称为Beas-2b-t。结果表明，BAP（6.25、12.5和25μm）的处理显着促进了BEAS-2B-T细胞的迁移和侵袭。同时，BAP暴露抑制了BEAS-2B-T，甲状腺相关指数FE2+，丙二醛（MDA），脂质过氧化（LPO）和反应性氧（ROS）的脂肪毒作用（ROS）显着降低。与铁毒相关的分子转铁蛋白受体（TFRC）的蛋白质水平显着降低，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）显着增加。铁肉食的干预极大地影响了BAP诱导的BEAS-2B-T的迁移和侵袭。此外，在BAP暴露后，YTH N6 N6-甲基腺苷RNA结合蛋白1（YTHDF1）的表达显着增加。 YTHDF1敲低通过促进铁毒性抑制了BEAS-2B-T迁移和侵袭。同时，Fe2+，MDA，LPO和ROS的含量显着增加，TFRC显着增加，SLC7A11，FTH1和GPX4显着下降。此外，YTHDF1的过表达通过抑制铁毒性促进了BEAS-2B-T迁移和侵袭。重要的是，击倒YTHDF1在BAP暴露期间促进了铁毒性，BEAS-2B-2迁移和入侵降低，而YTHDF1的过表达增加了通过抑制BAP暴露期间的铁tho虫来增加迁移和侵袭Beas-2b-t。 RNA免疫沉淀测定法表明，YTHDF1与SLC7A11和FTH1的结合显着增加了YTHDF1过表达。因此，我们得出的结论是，BAP通过上调SLC7A11和FTH1的YTHDF1促进了Beas-2b-T细胞的恶性进展，以抑制螺栓吞噬作用。这项研究揭示了用于预防和治疗环境致癌物诱导的肺癌的新表观遗传和铁凋亡标记。
Abstract
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 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 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.