Xu Siyi, Li Jie, Yang Sheng, Yang Panpan, Niu Yiru, Ge Yiling, Liang Geyu
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
Toxics. 2025 Apr 5;13(4):280. doi: 10.3390/toxics13040280.
Benzo[a]pyrene, as the primary component of air pollutants, has been implicated in the pathogenesis of non-small-cell lung cancer (NSCLC). As an m6A reader that facilitates mRNA translation, YTHDF1 serves as a crucial regulator in tumor progression. Therefore, we established Benzo[a]pyrene(B[a]P)-induced bronchial epithelial malignant transformed cells (HBE-P35) to simulate the precancerous lesions of NSCLC and investigated the regulatory axis of YTHDF1 in both HBE-P35 and A549 lung cancer cells. A high level of m6A expression was detected in both HBE-P35 and A549 cells. Over-expression of YTHDF1 was observed in NSCLC tissues and correlated with poor overall survival in NSCLC patients. TMT labeling-based proteomic analysis and clinical lung tissue microarray assays demonstrated that CDK6 and MAP3K6 were positively correlated with YTHDF1 expression. MeRIP and RIP analyses revealed that YTHDF1 mediates the m6A-dependent regulation of CDK6 and MAP3K6 protein expression. The acquisition and deletion of miR-139/145-5p, along with luciferase reporter gene assays, demonstrated that miR-139-5p can target YTHDF1. Therefore, we conclude that YTHDF1 regulates CDK6 and MAP3K6 through m6A in B[a]P-induced HBE-P35 and A549 cells, providing a potential target for lung cancer treatment.
苯并[a]芘作为空气污染物的主要成分，与非小细胞肺癌（NSCLC）的发病机制有关。作为一种促进mRNA翻译的m6A阅读器，YTHDF1在肿瘤进展中起着关键调节作用。因此，我们建立了苯并[a]芘（B[a]P）诱导的支气管上皮恶性转化细胞（HBE-P35）来模拟NSCLC的癌前病变，并研究了YTHDF1在HBE-P35和A549肺癌细胞中的调控轴。在HBE-P35和A549细胞中均检测到高水平的m6A表达。在NSCLC组织中观察到YTHDF1的过表达，并且与NSCLC患者的总体生存率低相关。基于TMT标记的蛋白质组学分析和临床肺组织芯片检测表明，CDK6和MAP3K6与YTHDF1表达呈正相关。MeRIP和RIP分析表明，YTHDF1介导了对CDK6和MAP3K6蛋白表达的m6A依赖性调控。miR-139/145-5p的获得和缺失以及荧光素酶报告基因检测表明，miR-139-5p可以靶向YTHDF1。因此，我们得出结论，YTHDF1在B[a]P诱导的HBE-P35和A549细胞中通过m6A调节CDK6和MAP3K6，为肺癌治疗提供了一个潜在靶点。
